ORIGINAL ARTICLE

Predicting the Progression of Palindromic to Rheumatoid : The Role of Ultrasonography and Anti-cyclic Citrullinated Peptide Antibodies

Hsin-Hua Chen1,2,3, Der-Yuan Chen1,2,3*, Tsu-Yi Hsieh1,2, Guo-Dung Hung1, Howard Haw-Chang Lan4,5,6, Chia-Wei Hsieh1, Joung-Liang Lan1,2,3,7

We investigated whether sonography and anti-cyclic citrullinated peptide (anti-CCP) anti- bodies in Chinese patients with palindromic rheumatism (PR) during active episodes are of predictive value for development of (RA). Clinically involved regions of 84 PR patients during active episodes were examined with ultrasonography using a 6–13 MHz linear transducer. Serum levels of anti-CCP antibodies were deter- mined by enzyme-linked immunosorbent assay. All patients were followed up monthly for 3 years after investigation. Thirteen (15%) of the PR patients had progressed to RA after a mean of 1.4 years (range, 0.4–3.0 years). Of these 13 patients, 11 patients (85%) had sonographic features of synovitis and 8 patients (62%) had a positive anti-CCP anti- body test. The absence of sonographic features of synovitis during active episodes pro- vided a very high 3-year predictive value in excluding the possibility of progression to RA for PR patients with a negative anti-CCP antibody test. Both the sonographic findings of synovitis and a positive anti-CCP antibody test were significant predictors for progression of PR to RA within 3 years by backward stepwise logistic regression analysis. Sonographic examination together with an anti-CCP antibody test during active episodes is useful for predicting the progression of PR to RA.

KEY WORDS — anti-cyclic citrullinated peptide antibodies, palindromic rheumatism, rheumatoid arthritis, sonographic findings

■ J Med Ultrasound 2010;18(1):17–26 ■

Received: June 22, 2009 Accepted: August 27, 2009 1Division of Allergy, Immunology and , Taichung Veterans General Hospital, Taichung, 2School of Medicine, National Yang-Ming University, Taipei, 3Institute of Medical Technology, National Chung-Hsing University, 4Department of Radiology, Taichung Veterans General Hospital, 5Central Taiwan University of Science and Technology University, 6Hungkuang University, Taichung, and 7School of Medicine, Taipei Medical University, Taipei, Taiwan. *Address correspondence to: Dr. Der-Yuan Chen, Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, 160 Taichung-Kang Road, Section 3, Taichung City, 40705, Taiwan. E-mail: [email protected]

©Elsevier & CTSUM. All rights reserved. J Med Ultrasound 2010 • Vol 18 • No 1 17 H.H. Chen, D.Y. Chen, T.Y. Hsieh, et al

Introduction Patients and Methods

Palindromic rheumatism (PR) is characterized by This study was approved by the Ethics Committee recurrent attacks of acute arthritis or periarticular of Clinical Research at Taichung Veterans General , lasting from a few hours to several Hospital (VGHTC). From January to July 2003, we days with variable symptom-free intervals, and pro- recruited patients who fulfilled the diagnostic cri- ducing no residual articular damage [1]. It is con- teria for PR as proposed by Guerne and Weismann troversial whether PR is a separate disorder or is a [10], and were suffering active episodes of PR as prodrome of rheumatoid arthritis (RA). A number determined by Dr. J.-L. Lan, D.-Y. Chen and T.-Y. of series of longitudinally followed-up PR patients Hsieh at the rheumatology outpatient clinic of showed that one third to one half of these cases VGHTC. When patients presented with acute on- evolved into RA [2–5]. Anti-cyclic citrullinated pep- set of painful swelling over articular or periarticular tide (anti-CCP) antibodies are highly specific for regions without preceding trauma, this was de- RA [6], and appear to be much more predictive of fined as an active episode. Crystal arthritis and the development of RA than (RF) infectious arthritis were excluded by synovial fluid [7,8]. Because recent reports highlight the early on- analysis if effusion was demonstrated by sono- set of structural articular damage in RA patients [9], graphic examination. A total of 84 PR patients were it could be important to separate PR patients from enrolled in this study. Thirty-two (38%) of these PR those who have the potential to develop RA. patients were treated with hydroxychloroquine As distinct clinical, laboratory or radiological only (200–400 mg daily) before their inclusion in markers have not yet been identified, the diagno- this study. Sixteen (19%) of the patients with PR sis of PR currently relies on clinical features and on during active episodes had more than one region excluding other forms of episodic arthritis [10]. of attack. We followed up the PR patients monthly The recent availability of high-frequency transduc- for 3 years at the outpatient clinic of VGHTC. ers (> 7.5 MHz) allows sonographic approaches to Antinuclear antibodies were screened by indi- the diagnosis and assessment of soft tissue involve- rect immunofluorescence using a Fluorhepana test ment in patients with rheumatic diseases [11–13]. kit (Medical & Biological Laboratories Co. Ltd., Kasukawa et al [14] reported that sonographic eval- Nagoya, Japan) with Hep-2 cells as the substrate. uation of synovial membrane proliferation in the The determination of anti-CCP antibody was per- knee joints of two PR patients could be used to formed by enzyme-linked immunosorbent assay identify conversion from PR to RA. Therefore, we using a commercial kit (INOVA Diagnostics Inc., hypothesized that sonographic evaluation may help San Diego, California, USA) [15]. A serum result predict the progression or non-progression of PR was considered positive for anti-CCP antibodies if to RA. However, there are no data on sonographic the titer was above 20 IU/mL. Serum levels of RF- findings of involved joints in a large number of PR immunoglobulin M (IgM) and C-reactive protein patients during active episodes. (CRP) were measured by nephelometry (Dade In this study, we described the sonographic Behring, Deerfield, Illinois, USA). A serum result findings of involved regions during active episodes was considered positive for RF when the level was and determined serum anti-CCP levels in a cohort above 22 IU/mL. of 84 unrelated Chinese PR patients. We followed Sonographic assessment of the clinically involved up these patients monthly for 3 years and investi- regions was performed with a General Electric gated whether sonographic findings and anti-CCP LOGIQ 500 unit (GE, Milwaukee, Wisconsin, USA) antibodies during active episodes can be of predic- using a 6–13 MHz linear array transducer. Gray-scale tive values for determining the progression to RA ultrasonography (US) and power Doppler US (PDUS) from PR. examinations of the involved regions during active

18 J Med Ultrasound 2010 • Vol 18 • No 1 Sonographic Findings in Palindromic Rheumatism episodes for PR patients were performed. The B-mode of sonographic patterns in the same patient, 20 frequency used was 11 MHz. The pulse repetition patients were examined for a second time during frequency of PDUS was set at 1 KHz with a low different active episodes in the 3 years following wall filter (150 Hz). The color gain of PDUS was the initial investigation. adjusted to a level just below that at which all Results are presented as the median [inter- color noise disappeared from regions deep to the quartile (IQ) range] for age at onset, disease dura- cortical bone echo in the corresponding image. tion, and CRP levels. The χ2 test and Fisher’s exact Pulsed Doppler spectra were performed to confirm test were used for testing differences in the fre- the presence of vessels when the images were un- quencies of categorical data between groups. The clear. We followed the guidelines for patient posi- Mann-Whitney U test was used to test differences tioning and standard scans that were advocated in continuous variables between groups. Backward by Backhaus et al in 2001 [16]. Assessment of local- stepwise logistic regression analysis was performed ized swelling or redness was carried out with longi- to determine the optimal model for the prediction tudinal and transverse planes to clarify its anatomy of progression of PR to RA. A p value of less than and relation to adjacent structures. The adjacent 0.05 was considered to be significant. Statistical joint was also assessed circumferentially to detect calculations were performed using the SPSS ver- any associated pathology, especially synovitis. Bilat- sion 13.0 (SPSS Inc., Chicago, Illinois, USA). eral comparison was carried out. The scans were performed by two rheumatologists (H.-H. Chen and G.-D. Hong) who were trained and experienced Results in musculoskeletal sonography. The examinations of each patient were performed independently Fifty-two (62%) patients with PR did not receive and sequentially on the same day. Each sonogra- any medication for at least 3 months prior to en- pher was blinded to the laboratory findings, as rollment in this study. Positive anti-CCP antibody well as to the sonographic findings of the other tests were observed in 11 (13%) patients with PR sonographer. They documented and stored digital during active episodes. Positive RF-IgM tests were images of any abnormalities that were noted. All observed in 12 (14%) of patients with PR during ultrasound images were read in a blinded manner active episodes. CRP levels were increased in 54 by a radiologist (H.H.-C. Lan) and a rheumatolo- (64%) patients with PR during active episodes. Low- gist (C.-W. Hsieh), who were both experienced in titer antinuclear antibodies (1:80–1:160) were found musculoskeletal ultrasonography. The interpreta- in six (7%) PR patients during active episodes. tion of the stored images was performed by con- Radiographs of all involved locations showed an sensus between the two readers. absence of bony erosion or joint space narrowing. The images were interpreted as showing syn- Patients were divided into two groups based on ovitis when effusion was present, or when an ab- the presence or absence of sonographic features of normal hypoechoic, intra-articular tissue that was synovitis. Thirty (36%) PR patients had sonographic non-displaceable, poorly compressible and possi- features of synovitis in any of the involved regions bly exhibiting Doppler signals was present within (Fig. 1). The remaining 54 (64%) PR patients dis- any of the involved joint capsules. Doppler signals played no sonographic features of synovitis in any were demonstrated in two planes and were con- of the involved regions (Fig. 2). Extra-articular soft firmed by pulsed wave Doppler spectrum to exclude tissue inflammation was observed in four of the 54 artifacts. Effusion was characterized by abnormal PR patients without synovitis (three over the left hypoechoic or anechoic intra-articular material that sole and one over the right palm). The other 50 of was displaceable and compressible but did not ex- the 54 patients without synovitis had sonographic hibit Doppler signals [17]. To test the consistency findings of tenosynovitis (tendon sheath thickening

J Med Ultrasound 2010 • Vol 18 • No 1 19 H.H. Chen, D.Y. Chen, T.Y. Hsieh, et al

*

R L C

MCP

Fig. 2. Sonographic image of the second metacarpophalangeal Fig. 1. Sonographic image of the right wrist in a patient with joint in a patient with palindromic rheumatism with peri- palindromic rheumatism with synovitis. Longitudinal scan articular inflammation from longitudinal scan on a standoff through the radius (R), lunate (L) and capitate (C) with a pad with power Doppler image. Note the abnormally thick- gray-scale image. *Note an abnormally thickened hypoechoic ened hypoechoic region (between the long arrows) and synovial membrane. Doppler signals over soft-tissue without involvement of the synovial membrane. MCP = metacarpophalangeal joint. that might exhibit Doppler signals in the involved regions, 32 patients) and/or peri-articular soft tis- no significant differences in age at onset, the pro- sue inflammation (an abnormally thickened hypo- portion of female, disease duration, frequency of echoic region over peri-articular soft tissue that Doppler signals and the proportion of use of hydroxy- could potentially exhibit abnormal Doppler signals chloroquine between PR patients with or without compared with those exhibited in the correspon- sonographic features of synovitis (Table 1). There ding contralateral region, 26 patients). Doppler was also no significant difference in the positive rate signals were shown by PDUS in 66 (78%) of the of anti-CCP antibody and RF-IgM tests between PR 84 PR patients. Joint effusion was shown in eight patients treated with hydroxychloroquine and those (27%) of 30 PR patients who had sonographic in patients not treated with hydroxychloroquine findings of synovitis. A thickened hypoechoic syn- before inclusion in the present study. ovial membrane was found in 29 (97%) of these CRP levels in PR patients whose PDUS images patients. No evidence of bone erosion was demon- exhibited abnormal Doppler signals were signifi- strated in any PR patients. cantly higher than those in PR patients whose PDUS A significantly higher positive rate of anti-CCP images did not exhibit these abnormal Doppler antibody [26.7% vs. 5.6%, odds ratio (OR) 6.18, signals (median, 1.0 mg/dL, IQ range, 0.7–1.6 mg/ 95% confidence interval (CI) 1.50–25.52, p = 0.014] dL vs. median, 0.2 mg/dL, IQ range, 0.1–0.3 mg/dL; and RF-IgM (30.0% vs. 5.6%, OR 7.29, 95% CI p < 0.001). CRP levels in PR patients who had sono- 1.79–29.60, p = 0.007) were observed in PR pa- graphic findings of synovitis with Doppler signals tients who had sonographic features of synovitis in thickened synovium were also significantly higher compared with those in PR patients without sono- than those in PR patients who had sonographic graphic features of synovitis (Table 1). CRP levels in findings of synovitis without Doppler signals in PR patients with sonographic features of synovitis thickened synovium (median, 1.0 mg/dL, IQ range, were slightly higher than those in PR patients with- 0.6–2.0 mg/dL vs. median, 0.37, IQ range, 0.24– out sonographic features of synovitis (median, 0.40 mg/dL; p = 0.007). There was no significant 1.0 mg/dL, IQ range, 0.5–2.0 mg/dL vs. median, difference in CRP levels between PR patients who 0.8, IQ range, 0.3–1.2 mg/dL; p = 0.05). There were had sonographic features of synovitis with effusion

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Table 1. Clinical characteristics vs. ultrasonography findings in palindromic rheumatism patients* Sonographic findings p OR (95% CI) Synovitis (–) (n = 54) Synovitis (+) (n = 30) Age at onset (yr) 40 (29–44) 37 (28–50) 0.751 Sex (M:F)† 18:36 10:20 1.000 1.00 (0.39–2.58) Disease duration (yr) 6.3 (3.9–11.8) 5.5 (2.8–10.6) 0.211 HCQ (+) (%)† 22 (40.7%) 16 (53.3%) 0.361 1.66 (0.68–4.09) Doppler signal (+) (%)† 40 (74.1%) 26 (86.7%) 0.268 2.28 (0.67–7.68) CRP (mg/dL) 0.8 (0.3–1.2) 1.0 (0.5–2.0) 0.050 CCP (+) (%)† 3 (5.6%) 8 (26.7%) 0.014 6.18 (1.50–25.52) RF (+) (%)† 3 (5.6%) 9 (30.0%) 0.007 7.29 (1.79–29.60)

*Values are median (interquartile range) unless designated otherwise; †Fisher’s exact test. OR = odds ratio; CI = confidence interval; M = male; F = female; HCQ = hydroxychloroquine; CRP = C-reactive protein; CCP = anti-cyclic citrullinated peptide antibody; RF = rheumatoid factor of Immunoglobulin M isotype. and PR patients who had sonographic features of progressed to RA (median, 7.0 years, IQ range, synovitis without effusion (median, 1.75 mg/dL, 4.0–12.0 years vs. median, 3.0 years, IQ range, IQ range, 0.5–2.3 mg/dL vs. median, 1.00 mg/dL, 1.3–7.4 years; p = 0.008; Table 2). A significantly IQ range, 0.48–1.50 mg/dL; p = 0.396). higher rate of progression to RA was observed in Twenty (24%) of the PR patients were available patients with sonographic features of synovitis com- to be examined for a second time during different pared with that in patients without sonographic active episodes within a mean interval of 7.9 months features of synovitis (37.7% vs. 3.7%, OR 15.05, (range, 1–34 months). Nine (45%) of them had so- 95% CI 3.05–74.23, p < 0.001). A significantly nographic features of synovitis. Eighteen (95%) of higher rate of progression to RA was also observed them had consistent sonographic patterns. In one in patients with positive anti-CCP antibody tests patient who had a negative anti-CCP antibody test than that in patients with negative anti-CCP anti- and had not progressed to RA during 3 years of body tests (72.7% vs. 6.8%, OR 36.27, 95% CI follow-up, the sonographic features shifted from 7.26–181.06, p < 0.001). A significantly higher rate the presence of synovitis to the absence of synovi- of progression to RA was observed in patients with tis 7 months after the first US scan. positive RF-IgM tests compared with that in pa- Thirteen (15%) of the PR patients had progressed tients with negative RF-IgM tests (66.7% vs. 6.9%, to RA after a mean of 1.4 years (range, 0.4–3.0 years). OR 26.80, 95% CI 5.95–120.76, p < 0.001). There Among them, 11 patients (85%) had sonographic were no significant differences in the frequency of features of synovitis, 8 patients (62%) had positive presence of effusion and Doppler signals detected anti-CCP antibody tests and 8 patients (62%) had by sonographic examinations, age at onset, the positive RF-IgM tests. One patient who had a neg- proportion of females, the proportion of use of ative anti-CCP antibody test and absence of sono- hydroxychloroquine before investigation and CRP graphic features of synovitis progressed to systemic levels between PR patients with progression to RA lupus erythematosus. The remaining 70 PR patients and those in patients without progression to RA were treated with hydroxychloroquine 200–400 mg (Table 2). daily unless remission lasted over 6 months. Of the 73 PR patients with negative anti-CCP The disease duration before investigation in PR antibody tests, a significantly lower rate of pro- patients who had not progressed to RA was signif- gression to RA was observed in patients who had icantly longer than that in PR patients who had no sonographic features of synovitis than that in

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Table 2. Clinical characteristics, and laboratory and sonographic findings for palindromic rheumatism patients with and without progression to rheumatoid arthritis (RA)* Progression to RA p OR (95% CI) Yes (n = 13) No (n = 71) Age at onset (yr) 49 (25–55) 39 (28–43) 0.370 Sex (M:F) † 5:8 23:48 0.752 0.77 (0.23–2.60) Disease duration (yr) 3.0 (1.3–7.4) 7.0 (4.0–12.0) 0.008 HCQ (+) (%)† 7 (40.7%) 16 (22.5%) 0.555 1.51 (0.46–4.93) Sonographic findings Synovitis (+)† 11 (84.6%) 19 (26.8%) < 0.001 15.05 (3.05–74.23) Effusion (+)† 3 (23.1%) 5 (7.0%) 0.103 3.96 (0.82–19.19) Synovial thickening (+) 11 (84.6%) 18 (25.4%) < 0.001 16.19 (3.27–80.11) Doppler signal (+)† 10 (76.9%) 56 (78.9%) 1.000 0.89 (0.22–3.66) CRP (mg/dL) 1.0 (0.4–2.6) 0.8 (0.4–1.2) 0.340 CCP (+) (%)† 8 (61.5%) 3 (4.2%) < 0.001 36.27 (7.26–181.06) RF (+) (%)** 8 (61.5%) 4 (5.6%) < 0.001 26.80 (5.95–120.76)

*Values are median (interquartile range) unless designated otherwise; †Fisher’s exact test. OR = odds ratio; CI = confidence interval; M = male; F = female; HCQ = hydroxychloroquine; CRP = C-reactive protein; CCP = anti-cyclic citrullinated peptide antibody; RF = rheumatoid factor of Immunoglobulin M isotype.

Table 3. Associations between anti-cycle citrullinated antibody/sonographic findings during active episodes and progression of palindromic rheumatism to rheumatoid arthritis (RA) within 3 years Progression to RA p OR (95% CI) Yes No CCP (–) Sonographic finding 0.002 – Synovitis (+)517 Synovitis (–) 0 51 CCP (+) Sonographic finding 1.000 1.50 (0.08–26.85) Synovitis (+)62 Synovitis (–) 2 1

OR = odds ratio; CI = confidence interval; CCP = anti-cyclic citrullinated peptide antibody.

patients who had sonographic features of synovitis antibody test and a positive RF-IgM test in relation (0% vs. 29.4%, Table 3, p = 0.002). Of the 11 PR to the subsequent development of RA within 3 years patients with positive anti-CCP antibody tests, there are shown in Table 4. We used backward logistic re- was no difference in the rate of progression to RA gression analysis to determine the optimal model between patients with sonographic features of syn- for the prediction of progression to RA within 3 years ovitis and that in patients without sonographic (Table 5). In this analysis, the presence of sono- features of synovitis (Table 3). graphic features of synovitis (OR 12.03, 95% CI The relative values of the presence of sono- 1.88–76.98, p = 0.009) and a positive anti-CCP anti- graphic features of synovitis, a positive anti-CCP body test (OR 3.74, 95%, CI 0.35–39.44, p < 0.001)

22 J Med Ultrasound 2010 • Vol 18 • No 1 Sonographic Findings in Palindromic Rheumatism

Table 4. Relative values of sonographic features of synovitis, anti-cyclic citrullinated peptide antibodies (CCP) and rheumatoid factor during active episodes in predicting progression of palindromic rheumatism to rheumatoid arthritis within 3 years Synovitis (+) Synovitis (+) Synovitis (+) and Synovitis (+) CCP (+) RF (+) or CCP (+) and CCP (+) CCP (+) and RF (+) Sensitivity 0.85 0.62 0.62 1.00 0.46 0.46 Specificity 0.73 0.96 0.94 0.72 0.97 0.99 Positive predictive value 0.37 0.73 0.67 0.39 0.75 0.86 Negative predictive value 0.96 0.93 0.93 1.00 0.91 0.91 Positive likelihood ratio 3.16 14.56 10.92 3.55 16.39 32.77 Negative likelihood ratio 0.21 0.40 0.41 0 0.55 0.55

RF = rheumatoid factor of immunoglobulin M isotype.

Table 5. Results of backward stepwise logistic regression analysis for determination of the optimal model for the prediction of progression of palindromic rheumatism to rheumatoid arthritis within 3 years Significant variable OR (95% CI) p Excluded variables Synovitis (+) 12.03 (1.88–76.98) 0.009 Synovial thickening (+) CCP (+) 28.99 (4.52–185.91) < 0.001 Effusion (+) Doppler signal (+) RF (+)

OR = odds ratio; CI = confidence interval; CCP = anti-cyclic citrullinated peptide antibody; RF = rheumatoid factor of immunoglobulin M isotype. were both significant variables for the prediction of Periarticular inflammation, which often presents progression of PR to RA within 3 years. However, with swelling as well as redness and may involve the presence of sonographic findings of synovial the joint structure, was observed in approximately thickening, effusion, the presence of abnormal 30% of PR patients in previous studies [1,5], whereas Doppler signals detected by PDUS and a positive a higher occurrence rate (64%) was shown by so- RF-IgM test were excluded from the optimal model nography in our PR patients. Consistent with the for the prediction of progression of PR to RA within findings of other reports [18–20], an improved 3 years. sensitivity in the detection of periarticular inflam- mation using high-resolution US may have con- tributed to this discrepancy between studies. In Discussion the present study, the mean duration from onset of symptoms to development of RA was 6.6 years. To our knowledge, the present study is the first to Thirty (36%) of the PR patients in the present attempt to assess sonographic findings in a large study showed sonographic features of synovitis number of PR patients during active episodes. The (Fig. 2B). Twenty patients (87%) exhibited Doppler distribution of the joints involved in our patients signals in the thickened synovium on PDUS images. was similar to that in previous reports [1–5]. When The introduction of PDUS allows the detection of patients present clinically with swelling and red- smaller degrees of synovitis with a reported accu- ness around the joint, it is often difficult to define racy equal to that of dynamic MRI [21]. Using his- anatomic changes of the involved region by cli- topathology as gold standard, Koski et al [22] found nical examination or conventional radiography. that a negative Doppler signal did not exclude the

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possibility of synovitis and a positive Doppler signal to progression of PR to RA limits the use of disease in the synovium was an indicator of an active syn- duration in predicting progression of PR to RA. Some ovial inflammation in patients. Moreover, a signifi- investigators have attempted to search for biologic cant correlation between the power Doppler signal markers that might predict the progression to RA and the degree of vascularity of the synovial tissue in PR patients. Recently, a positive anti-CCP anti- has recently been reported [23]. In our study, we body test was found to be highly specific for RA found significantly higher CRP levels in PR patients [6], and it appears to be much more predictive of with sonographic features of synovitis who had the development of RA than RF [7]. Doppler signals in the synovium compared with In the present study, we followed up our PR patients who did not have Doppler signals in the patients for 3 years after US examinations and anti- synovium, and this could be because of the pres- CCP antibody tests during active episodes. Only ence of more active synovial inflammation in these 15% of our PR patients had progressed to RA. The patients. rate of progression to RA in our PR patients is lower There is no standard laboratory test to diagnose than that reported previously [8,23]. This disparity PR. In our study, 54 (64.3%) of the patients with may be because of a longer disease duration PR had elevated CRP levels during active episodes. before investigation, population characteristics or The significantly higher CRP levels in PR patients shorter duration of follow-up. However, the mean with sonographic features of synovitis compared duration (6.6 years) from onset of symptoms to with patients without sonographic features of syn- development of RA in our PR patients is consistent ovitis suggests a higher degree of inflammation in with data reported previously [7,8]. synovitis. However, CRP is neither specific nor sen- The positive predictive value was 73% for a sitive enough for the diagnosis of PR. The lower positive anti-CCP antibody test in our study, which positive rate of anti-CCP antibodies in our patients is consistent with previous data [8]. The high than those reported previously [8,24] may be due specificity and negative predictive values for a pos- to a longer mean ± SD disease duration (8.2 ± 6.4 itive anti-CCP antibody test are also consistent years) before investigation in our PR patients (which with previous reports [27,28]. We found that the may have excluded some PR patients who pro- negative predictive value was high for both the gressed more rapidly to RA), and population char- presence of sonographic features of synovitis and a acteristics or target epitopes of citrulline used in positive anti-CCP antibody test. We found that in the detection method. PR patients with a negative anti-CCP antibody In the present study, a lower positive rate of anti- test, there was a significantly lower rate of pro- CCP antibodies was found in patients with no sono- gression to RA in those patients without sono- graphic features of synovitis. In contrast, a higher graphic features of synovitis compared with that positive rate of anti-CCP antibodies was observed in those with sonographic features of synovitis in patients with sonographic features of synovitis. (Table 3). The absence of sonographic features of Accumulating evidence suggests that the immune synovitis during active episodes provided a very response to citrullinated peptides could play a sig- high 3-year predictive value in excluding the possi- nificant role in the pathogenesis of synovitis in RA bility of progression to RA for PR patients with a [25,26]. However, this hypothesis needs to be con- negative anti-CCP antibody test. In addition, we firmed by further investigation and a large prospec- used backward logistic regression analysis to deter- tive cohort study. mine the optimal model for the prediction of pro- A longer disease duration was found in our PR gression of PR to RA within 3 years and found that patients who had not progressed to RA compared both the presence of sonographic features of syn- with that in patients who had progressed to RA. ovitis and a positive anti-CCP antibody test were However, the wide variation of duration from onset significant variables. Therefore, the sonographic

24 J Med Ultrasound 2010 • Vol 18 • No 1 Sonographic Findings in Palindromic Rheumatism findings of involved regions in PR patients during 3. Williams MH, Sheldon PJ, Torrigiani G, et al. active episodes could be valuable for helping clini- Palindromic rheumatism. Clinical and immunologi- cians to predict future development of RA within cal studies. Ann Rheum Dis 1971;30:375–80. 3 years. 4. Wajed MA, Brown DL, Currey HL. Palindromic rheumatism. Clinical and serum complement study. Some limitations of our study should be high- Ann Rheum Dis 1977;36:56–61. lighted. First, our study was conducted in ac- 5. Hannonen P, Mottonen T, Oka M. Palindromic cordance with daily clinical practice. Patients were rheumatism. A clinical survey of sixty patients. Scand J treated without hydroxychloroquine or with various Rheumatol 1987;16:413–20. doses of hydroxychloroquine before recruitment 6. Bizzaro N, Mazzanti G, Tonutti E, et al. Diagnostic and during the 3-year follow-up period. Therefore, accuracy of the anti-citrulline antibody assay for we could not compare the predictive value of PDUS rheumatoid arthritis. Clin Chem 2001;47:1089–93. variables depending on the medication received. 7. Dahlqvist SR, de Jong BAW, Berglin E, et al. Antibodies against citrullinated peptides (CCP) and Second, we were not always able to perform US immunoglobulin-A rheumatoid factor predict the scanning when patients presented active episodes; development of rheumatoid arthritis. Arthritis Rheum we only performed US scanning when patients 2003;48:2741–9. happened to have active episodes during their 8. Russell AS, Devani AL, Maksymowych AP. The role scheduled follow-up. Therefore, the data about of anti-cyclic citrullinated peptide antibodies in the consistency of the sonographic patterns in the predicting progression of palindromic rheumatism same patient were limited. to rheumatoid arthritis. J Rheumatol 2006;33: In conclusion, our results demonstrate that sono- 1240–2. graphic examination, which is a quick, inexpensive, 9. Hulsmans HMJ, Jacobs JWG, van der Heijde DMFM, et al. The course of radiologic damage during the and easily accessible technique for assessment of first six years of rheumatoid arthritis. Arthritis Rheum synovial and periarticular tissues of PR patients dur- 2000;43:1927–40. ing active episodes, together with a test for anti- 10. Guerne PA, Weisman MH. Palindromic rheumatism: CCP antibody are useful for predicting progression part of or apart from the spectrum of rheumatoid to RA within 3 years. arthritis. Am J Med 1992;93:451–60. 11. Grassi W, Tittarelli E, Pirani O, et al. Ultrasound ex- amination of metacarpophalangeal joints in rheuma- Acknowledgments toid arthritis. Scand J Rheumatol 1993;22:243–7. 12. Wakefield RJ, Gibbon WW, Conaghan PG, et al. The value of sonography in the detection of bone erosions We wish to thank the Biostatistics Task Force of in patients with rheumatoid arthritis: a comparison VGHTC, Taichung, Taiwan, ROC, for assistance with conventional radiography. Arthritis Rheum 2000; with statistical analysis. 43:2762–70. 13. Hau M, Schultz H, Tony HP, et al. Evaluation of pan- nus and vascularization of the metacarpophalangeal References and proximal interphalangeal joints in rheumatoid arthritis by high-resolution ultrasound (multidimen- 1. Hench PS, Rosenberg EF. Palindromic rheumatism. sional linear array). Arthritis Rheum 1999;42:2303–8. A “new” often recurring disease of joints (arthritis, 14. Kasukawa R, Takeda I, Iwadate H, et al. Ultrasono- periarthritis, para-arthritis) apparently producing no graphic evaluation of knee joint synovitis in two pa- articular residues. Report of thirty-four cases; its tients with palindromic rheumatism. Mod Rheumatol relation to “angio-neural arthrosis”, “allergic rheuma- 2002;12:230–4. tism”, and rheumatoid arthritis. Arch Intern Med 15. Schellekens GA, de Jong BAW, van den Hoogen FHJ, 1994;73:293–321. et al. Citrulline is an essential constituent of antigenic 2. Mattingly S. Palindromic rheumatism. Ann Rheum Dis determinants recognized by rheumatoid arthritis- 1966;25:307–17. specific autoantibodies. J Clin Invest 1998;101:273–81.

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16. Backhaus M, Burmester GR, Gerbert T, et al. evaluating the performance of ultrasound equip- Guidelines for musculoskeletal ultrasound in ments. Ann Rheum Dis 2006;65:1590–5. rheumatology. Ann Rheum Dis 2001;60:641–9. 23. Walther M, Harms H, Krenn V, et al. Correlation of 17. Wakefield RJ, Balint PV, Szkudlarek M, et al. Muscu- power Doppler sonography with vascularity of the syn- loskeletal ultrasound including definitions for ultra- ovial tissue of the knee joint in patients with osteo- sonographic pathology. J Rheumatol 2005;32:2485–7. arthritis and rheumatoid arthritis. Arthritis Rheum 18. Backhaus M, Kamradt T, Sandrock D, et al. Arthritis 2001;44:331–8. of the finger joints: a comprehensive approach com- 24. Salvador G, Gomez A, Viñas O, et al. Prevalence and paring conventional radiography, scintigraphy, ultra- clinical significance of anti-cyclic citrullinated peptide sound, and contrast-enhanced magnetic resonance and antikeratin antibodies in palindromic rheumatism. imaging. Arthritis Rheum 1999;42:1232–45. An abortive form of rheumatoid arthritis? Rheumatol 19. McGonagle D, Conaghan PG, Wakefield R, et al. 2003;42:1–4. Imaging the joints in early rheumatoid arthritis. Best 25. Masson-Bessiere C, Sebbag M, Girbal-Neuhauser E, Pract Res Clin Rheumatol 2001;15:91–104. et al. The major synovial targets of the rheumatoid 20. Szkudlarek M, Court-Payen M, Jacobsen S, et al. arthritis-specific antifilaggrin autoantibodies are de- Interobserver agreement in ultrasonography of the iminated forms of the alpha- and beta-chains of fibrin. finger and toe joints in rheumatoid arthritis. Arthritis J Immunol 2001;166:4177–84. Rheum 2003;48:955–62. 26. Vossenaar ER, Nijenhuis S, Helsen MM, et al. Citrulli- 21. Szkudlarek M, Court-Payen M, Strandberg C, et al. nation of synovial proteins in murine models of rheu- Power Doppler ultrasonography for assessment of matoid arthritis. Arthritis Rheum 2003;48:2489–500. synovitis in the metacarpophalangeal joints of pa- 27. Raza K, Breese M, Nightingale P, et al. Predictive tients with rheumatoid arthritis: a comparison with value of antibodies to cyclic citrullinated peptide dynamic magnetic resonance imaging. Arthritis Rheum in patients with very early . 2001;44:2018–23. J Rheumatol 2005;32:231–8. 22. Koski JM, Saarakkala S, Helle M, et al. Power Doppler 28. Ates A, Karaaslan Y, Aksaray S. Predictive value of anti- ultrasonography and synovitis: correlating ultra- bodies to cyclic citrullinated peptide in patients with sound imaging with histopathological findings and very early arthritis. Clin Rheumatol 2007;26:499–504.

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