ORIGINAL ARTICLE THE DIAGNOSIS OF EARLY RHEUMATOID ARTHRITIS USING MUSCULOSKELETAL ULTRASONOGRAPHY

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1 AL-AZHAR ASSIUT MEDICAL JOURNAL ORIGINAL ARTICLE THE DIAGNOSIS OF EARLY RHEUMATOID ARTHRITIS USING MUSCULOSKELETAL ULTRASONOGRAPHY Sonya M. Rashad, Eman A.M. Alkady, Essam A.M. Abda and Marwa A.A. Galal, Rheumatology and Rehabilitation Department, Faculty of Medicine, Assiut University, Egypt. ABSTRACT BACKGROUND: Early diagnosis is essential for the optimal treatment of rheumatoid arthritis (RA). Conventional X-rays only visualize the late signs of the disease outcome. There are evidences that magnetic resonance imaging (MRI) and musculoskeletal ultrasonography (MSUS) are sensitive in detection of early inflammatory and destructive changes in RA. OBJECTIVE: This study was performed to compare the effectiveness of MSUS with MRI in early detection of hands and feet joints involvement in early RA. SUBJECT and METHODS: Forty patients with early RA (less than 12 months disease duration and no visible erosion in their conventional X-ray) were subjected to a detailed MSUS examination in a minimum of two planes (longitudinal and transverse) of both hands and feet joints. Eighty radio-carpal, 320 MCPs (excluding the 1 st MCPs), 400 PIPs, 80 ankles, and 400 MTPs joints were examined for the presence of synovial thickening, effusion and erosions on initial evaluation and after 6 months. MRI examination of the hands and feet was arranged to be done at the same appointment of MSUS examination. RESULTS: Hand arthritis was detected in 38 patients (95%) by MSUS in comparison to 34 patients (94.4%) by MRI on initial evaluation. After 6 months, 119

2 Sonya M. Rashad et al all patients had hand arthritis by MSUS and MRI with 100% sensitivity and specificity of MSUS and MRI. Foot arthritis was detected in 34 patients (85%) by MSUS and was comparison to 32 patients (88.9%) by MRI on initial evaluation. On follow up evaluation, all patients had foot arthritis by MSUS compared to 28 (90.3%) patients by MRI. Sensitivity and specificity of MSUS compared to MRI in detecting feet arthritis were 93.75% and 100% respectively. Hand bone erosions were detected in 11 patients (27.5%) and foot bone erosions in 13 patients (32.5%) by MSUS, compared to 12 patients (33.3%) in hand and 9 patients (25%) in foot by MRI. Thirteen patients (36.1%) had hand and foot erosions after 6 months by MSUS, hand erosions were detected in 9 patients (31%) and foot erosions in 13 patients (41.9%). MSUS was 58.33% sensitive, and 91.67% specific in detection of hand erosions, 100% sensitive and 85.19% specific in detecting foot erosions compared to MRI. CONCLUSION: MSUS is effective as MRI in early diagnosis of RA. It might be considered a good negative indicator of hand erosions. INTRODUCTION The therapeutic approach to RA has changed over the last two decades (Duxneuner, 2010). On the base of window of opportunity concept, diagnosis of RA, as early as possible, is essential to identify those patients who will progress to more severe forms, and therefore require more aggressive therapy (de Mota, et al., 2010). Keystone et al, (2004), and Klareskog et al (2009) postulated that erosive progression in RA is arrested, and occasionally even reversed, when starting methotrexate and tumor necrosis factor alpha (TNF-α) antagonist therapy early. Advanced imaging modalities, such as MRI and MSUS, allow direct visualization of early inflammatory and destructive joint changes in RA. They could capture disease manifestations responsible for patient disability before 120

3 AL-AZHAR ASSIUT MEDICAL JOURNAL conventional radiography (CR). In addition, they are considered objective tools for monitoring the joint and soft tissue inflammation and bone damage (Klarlund et al., 2000; Lindegaard et al., 2001; Østergaard et al., 2005 (a); da Mota et al., 2010; Platzgummer, Weidekamm, 2012). Measurement of inflammation activity represents the basis of therapeutic decision. It can be determined quantitatively and qualitatively by MRI and MSUS (Platzgummer, Weidekamm, 2012). Moreover, inflammatory changes on MRI and MSUS were predictive for erosive progression (Døhn et al, 2011). So, we aimed in this study to compare the effectiveness of MSUS with MRI in early detection of hands and feet joints involvement in early RA. SUBJECT AND METHODS: Forty RA patients, attending the Rheumatology, Rehabilitation & Physical medicine outpatient clinic in Assiut University Hospitals, were diagnosed according to the revised ACR criteria for the classification of Rheumatoid Arthritis (Arnett et al,1988) with a disease duration less than 12 months and absence of radiological erosion in their conventional X-rays. Baseline data included age, sex, disease duration, duration of morning stiffness, severity of arthritis, number of swollen and tender joints, assessment of their general heath with visual analogue scale (VAS) of100 mm and current medication. A blood sample was taken for erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum rheumatoid factor (RF) at baseline and at 6 months. A Postero-anterior (PA) radiographs of both hands and feet were performed at the beginning of the study for all patients to assure the absence of erosion by evaluating joint destruction according to Modified Larsen score (Larsen, 1995). 121

4 Sonya M. Rashad et al Musculoskeletal Ultrasound (MSUS) assessment: A detailed MSUS examination (GE LOGIQ 3 digital US scanner, MHz transducer) in a minimum of two planes (longitudinal and transverse) was done. In hands and wrists the following joints were evaluated systematically; the radio-carpal, metacarpo-phalangeal (MCP) and proximal inter-phalangeal (PIP) joints (with the exclusion of 1 st MCP). The ankle joint was evaluated for presence of effusion or synovitis, followed by the tarso-metatarsal (TMT) and metatarso-phalangeal (MTP) joints. The diagnosis of MSUS was based on that: Arthritis: which refers to synovial thickening,(defined as synovial hypertrophy which appears as a hypoechoic tissue that is not displaceable and poorly compressible and may exhibit Doppler signal (Wakefield, et al., 2005)), with or without effusion, (which refers to synovial fluid, and appears as an abnormal hypoechoic or anechoic intra-articular material that was displaceable and compressible and did not exhibit Doppler signal (Wakefield, et al., 2005)), in order to compare MSUS results with that obtained using plain MRI. Erosion: which express sign of destruction, and was based on the OMERACT definition of erosion as an intra-articular discontinuities of the bone surface visible in two perpendicular planes (Wakefield, et al., 2005). Quantification methods: o Arthritis: 122

5 AL-AZHAR ASSIUT MEDICAL JOURNAL We considered arthritis when either synovial thickening/effusion or both were present and no arthritis if neither synovial thickening nor effusion is present. o Erosion: A binary scoring system was used (Scheel, et al., 2006): 0=absent, and 1=present. Magnetic resonance imaging (MRI) assessment: MRI examinations for the hand and wrist joint were performed on a 1.5-T superconducting magnet (Gyroscan, Philips, The Netherlands). A standard MRI protocol covering the whole hand was adopted for all patients including fast spin-echo T2-weighted images and STIR-weighted sequences acquired in the coronal and axial planes using appropriate parameters using 3-mm slice thickness and a slice gap of 1 mm. A surface coil was used in all cases, with a 20cm field-of-view. The patient was examined lying in prone position, with the hand to be examined extended above the head into the magnet (superman position). No contrast was given to any of the patients. A standard MRI protocol covering the ankle and foot consisted of sagittal and coronal fast spin-echo T2-weighted images and STIR-weighted sequences using appropriate parameters to obtain 3-mm slice thickness and a slice gap of 1 mm in a 22-25cm field of view. 123

6 Sonya M. Rashad et al The patient was examined lying in the supine feet first position, and the foot to be examined placed inside a bird-cage type volume coil in plantar flexion. The obtained MRI images of the hands and wrists were evaluated according to the recommendations of the Outcome Measures in Rheumatology (OMERACT) MRI Task force (Østergaard, et al.,2003; Østergaard, et al., 2005(b)) : Erosion: signs of destruction (articular surface erosions), and Arthritis: signs of inflammation (the presence of synovial thickening, bone marrow edema). The obtained MR images of the ankles and feet were analyzed for signs of inflammation and destruction, and the images of the foot were analyzed in a similar way to that of the hands and wrists. MRI examination of the hands and feet was arranged to be done at the same appointment of MSUS examination. The obtained images of MSUS & MRI were recorded on hardcopy media. Both MSUS and MRI evaluation of both hands and feet joints included: 80 radio-carpal, 320 MCPs, 400 PIPs, 80 ankles, and 400 MTPs joints. at each visit (initial visit and after 6 months). Statistical analysis: Data were collected and analyzed using the Statistical Package for the Social Sciences (SPSS 16.0, SPSS Inc., and Chicago, USA). 124

7 AL-AZHAR ASSIUT MEDICAL JOURNAL Chi-Square tests was used for comparison between both initial and follow up results regarding MSUS and MRI outcomes (where P-value of <0.05 was considered statistically significant). Comparing the sensitivity and specificity of MRI and MSUS results, receiver-operating characteristic (ROC) curve analysis was used. RESULTS Forty early rheumatoid arthritis (ERA) patients were included at the start of that study, 4 patients were dropped out from the study, and only 36 patients continued the research. Note: 1. On initial MRI, 4 patients were missed due to low quality of their MRI, 2. On follow up, 29 patients were subjected to hand MRI, 4 didn't continue the research, 4 refused to repeat their MRI and 3 got pregnant during the time of research, 3. In feet follow up,31 patients were subjected to MRI, 4 didn't continue the research, 2 refused to repeat their MRI and 3 got pregnant during the time of research. Clinical and demographic data: Their ages ranged from (24-59) years with a mean age of (35.20 ± 8.75). Thirty eight patients were females (95%). The disease duration ranged from (2-12) months with a mean of (6.65 ± 6.48), as shown in table (1). 125

8 Sonya M. Rashad et al Table (1): Demographic, clinical and laboratory characteristics of 40 patients with ERA Variables No = 40 % Age (Mean ± SD) (Range), years (35.20 ± 8.75) (24 59) - Sex (Female) 38 95% Disease duration (Mean ± (6.65 ± 6.48) (2 12) SD)(Range), months Duration of morning stiffness (hours) o < 1 hour o 1 hour Drug treatment 1. DMARDs: o Monotherapy: (29) (14) 52.5% 47.5% (72.5%) 35% o Combination therapy: 2. NSAIDs: 3. Steroid: Detection of joint inflammation: (15) (32) (11) 37.5% (80%) (27.5%) Figure (1) Comparison of arthritis detection between MSUS/ MRI of (initial visit) 126

9 AL-AZHAR ASSIUT MEDICAL JOURNAL Figure (2) Comparison of arthritis detection between MSUS/ MRI of (follow up visit) At baseline, 38 patients (95%) had hand arthritis by MSUS as compared to 34 patients (94.4%) by MRI, and on follow up 6 months visit, all patients had hand arthritis by MSUS in comparison to 29 patients by MRI, (Figure 1). In addition, 34 patients (85%) had feet arthritis by MSUS compared to 32 patients (88.9%) with the use of MRI on initial evaluation, and after 6 months all patients had arthritis in their feet (detected by MSUS) compared to 28 (90.3%) patients by MRI, (Figure 2). For further comparison of both imaging techniques, we used the sensitivity/specificity equations to test the probable effectiveness of MSUS in identification of joints arthritis or not (using the MRI as a reference). 127

10 Sensitivity Sensitivity AAMJ, VOL (12), NO (2), APRIL 2014 Sonya M. Rashad et al 100 Arthiritis.hand.US Specificity Figure (3): sensitivity/specificity of arthritis in the hand joints Regarding hand arthritis detection, we found that MSUS was 100% sensitive and specific as MRI, (Figure 3). 100 Arthritis.foot.US Specificity Figure (4): sensitivity/specificity of arthritis in the feet joints. While, in feet arthritis, as shown in Figure 4, MSUS has a sensitivity of 93.75% and 100% specificity when compared to MRI. 128

11 AL-AZHAR ASSIUT MEDICAL JOURNAL Detection of joint destruction: Regarding the comparison between MSUS and MRI erosion detection in both hands and feet joints, initially and after 6 months follow up, the following was observed, Figure (5) Comparison of erosion detection between MSUS/ MRI of (initial visit) Figure (6) Comparison of erosion detection between MSUS/ MRI of (follow up visit) On initial visit, MSUS detected hand erosions in 11 patients (27.5%) and feet erosions in 13 patients (32.5%) compared to 12 patients (33.3%) in hands and 129

12 Sensitivity Sensitivity AAMJ, VOL (12), NO (2), APRIL 2014 Sonya M. Rashad et al 9 patients (25%) in feet by MRI. After 6 months, 13 patients had hands and feet erosions by MSUS in comparison to MRI which detected only 9 patients (31%) with hand erosions while 13 patients (41.9%) had feet erosions, (Figures 5 and Figure 6). 100 Erosion.hand.US Specificity Figure (7): sensitivity/specificity of erosions in the hand joints On further comparison of both imaging techniques (using the MRI as a reference), it was found that MSUS has a % sensitivity as well as % specificity as MRI in detecting hand erosions, (Figure 7). 100 Erodion.foot.US Specificity Figure (8): Sensitivity/specificity of erosions in the feet joints. 130

13 AL-AZHAR ASSIUT MEDICAL JOURNAL While in foot erosions, MSUS was as sensitive as MRI (100%) but was % specific as compared to MRI, (Figure 8). DISCUSSION Rheumatoid arthritis (RA) as a chronic inflammatory autoimmune debilitating disease leads to destructive progression, severe disability and premature mortality (Rantapaa-Dahlqvist et al,2003; Firestein,2003; Nielen et al,2004; Smolen et al,2005; Aletaha et al,2010). Physical examination is still considered the gold standard to identify the presence of arthritis. It became apparent that modern imaging techniques such as MSUS and MRI are more sensitive than physical examination in detecting joint injury in patients with RA, especially early-stage RA (McQueen, 2008; Aletaha et al., 2010; Tamai et al, 2011; Platzgummer and Weidekamm, 2012; Kawashiri et al., 2013). So, the current study was performed to compare the effectiveness of MSUS with MRI in early detection of hands and feet joints involvement in early RA (ERA). In our study, we reported that hand arthritis was detected in 38 patients (95%) on initial detection by MSUS, RC and 2 nd - 4 th MCPs were the most commonly affected joints early in RA, and all the hand joints were of mild or moderate degree except for RC joint where severe effusion was noted. In this study, foot arthritis was initially detected in 34 patients (85%). Ankles and 2 nd MTP were the first joints affected early in the disease. The 1 st MTP results were excluded in our study according to 2010 ACR/EULAR criteria because of its wide-range differential diagnosis (Aletaha et al, 2010). Regarding synovial thickening of the feet, Szkudlarek and his colleagues, (2004) stated that MSUS enables detection and grading of inflammatory changes (as well as destructive changes) in the MTP joints of RA patients. 131

14 Sonya M. Rashad et al As regard MRI data, the current result showed that RC, 2 nd - 4 th MCPs, ankles and 2 nd MTP were the common inflamed joints early in the disease. Moreover, 94.4 % and 88.9%of patients with hand and feet arthritis respectively in their initial visits by MRI. On follow up, all the evaluated patients (i.e. 100%) and 90.3% had hand and feet arthritis respectively. These differences between initial and follow up visits and the more frequent hands affection than feet, is believed to be due to the decreased number of patients who continued MRI follow up. Calisir et al (2007) were supportive to our results, they stated that feet involvement is a frequent occurrence in ERA. However, no significant difference between the MCP and MTP joints involvement with respect to RAbased changes obtained in the MRI was reported. By MSUS, the present study reported that hand bone erosions were detected in 11 patients (27.5%) on initial evaluation. RC, 2 nd MCP and 2 nd MTP were the most common affected joints with erosions. On follow up, 13 patients (36.1%) recorded hand erosions. The number of erosions was also increased in the Rt. RC and Rt. 4th PIP, while other joints remained the same. Meanwhile, foot bone erosions were recorded in 13 patients (32.5% & 36.1%) initially, and on follow up respectively. These data was in agreement with Bajaj et al 2007 study, who detected 15 erosions,by MSUS, in 10 patients at baseline (17 times more erosions than radiographs), and 31 erosions in 12 patients (57%) after 6 months. Wakefield et al, (2000) reported that the capability of MSUS in erosion detection may be contributed to: 1. The 3-dimensional capability of sonographic imaging allowed joints to be examined in several different planes; 2. Sonographic imaging was able to detect smaller erosions. In this study, some erosions detected (by MSUS) on initial visit, disappeared in the follow up visits. We believed that it might be due to misinterpretation in reading the erosion, especially when these erosions were 132

15 AL-AZHAR ASSIUT MEDICAL JOURNAL not confirmed by MRI. This misinterpretation might be attributed to the MSUS transducer position, as it cannot be positioned perpendicular to the area of interest, then the sound waves cannot be reflected back to the transducer, resulting in missing the erosions. This is known as the "acoustic window" of US (Wakefield et al., 2000). Also, Døhn and his team (2006) observed 'false positive' erosions in four healthy control individuals by MSUS. They considered these false positive results consistent with small well defined bone defects at the dorsal aspect of the metacarpal head. This was consistent with Boutry et al, (2004). Moreover, these may account for the lack of standardized definitions of pathology in MSUS. This fortifies the concept that MSUS is not sensitive method as MRI in erosion assessment as reported by Backhaus et al in 1999 and Hoving et al, (2004). Meanwhile, concerning erosions detection by MRI, Inter-carpal, 2 nd MCP and 2 nd MTP were the commonly affected joints. Initial evaluation showed hand erosions in 12 patients (33.3%) and feet erosions in 9 patients (25%). After 6 months, only 9 patients (31%) had hand erosions while 13 patients (41.9%) had feet erosions. We believed that the discrepancy in number of erosions is due to the decreased number of patients who refused to continue the MRI follow up, which is considering one of the drawbacks of MRI usage. In agreement to our data, also Tamai et al, (2011) postulated that plain MRI is effective in identifying bone lesions in the wrist and finger joints in ERA. They stated that MRI is not only a sensitive tool that reflects the joint injury in ERA patients, but also an accurate one. The degree of MSUS effectiveness in early detection of joint involvement in ERA has been a matter of argument especially when compared to MRI. According to our results, MSUS initially detected hand erosions in 11 patients (27.5%) and feet erosions in 13 patients (32.5%) in comparison to 12 patients (33.3%) in hands and 9 patients (25%) in feet as detected by MRI. On the other 133

16 Sonya M. Rashad et al hand, 13 patients had hands and feet erosions was found on MSUS follow up compared to only 9 patients (31%) with hand erosions as detected by MRI, and13 patients (41.9%) with feet erosions. Therefore, it is not surprising to find some difference favoring early MSUS erosions detection than MRI. These difference might be contributed to technical features such as, accessibility for ultrasonography examination, high resolution of ultrasonography assessment, or thickness of the MRI slices (use of relatively large MRI slices), rather than the physical principles of the examinations (Szkudlarek et al, 2006). MSUS was documented to have a 100% sensitivity and specificity detection of hand arthritis compared to MRI. It also showed 93.75% sensitivity and 100% specificity in feet arthritis detection in comparison to MRI. Other investigators were consistent with our results as they reported that MSUS is considered a sensitive soft tissue inflammation detector even in subclinical inflammation (Backhaus et al., 1999; Hoving et al., 2004; Bajaj et al., 2007; Rahmani et al., 2010). On contrast to previous studies, MSUS is not an ideal or a sensitive technique for early detection of bone erosion compared to MRI. But it might be considered a valuable tool for this purpose when MRI is not available or affordable (Backhaus et al.,1999; Hoving et al., 2004; Bajaj et al., 2007; Rahmani et al., 2010). In current study, MSUS showed 58.33% sensitivity in comparison to MRI in detection of hands erosion and 100% sensitivity in detection of feet erosion. The most probable cause of these results (sensitivity and specificity) is the dropped patients who did not perform the MRI (for different reasons). Therefore, these patients were also excluded in the statistical tests causing such high agreement between MSUS and MRI results. This must be taken in consideration as one of the limitations against the use of MRI, adding to 134

17 AL-AZHAR ASSIUT MEDICAL JOURNAL purposes recorded by Sutter et al, (2011) against its widespread use in prognosis of ERA. This study has some limitations. The relatively small sample size, in addition to the number of dropped patients, which affected some of our results, especially concerning the comparison between MSUS and MRI, which made the MSUS as sensitive (even specific) as MRI. The current study was confronted with some difficulties concerning imaging techniques. On performing MSUS, we were challenged by the low frequency of the machine. In addition to the lack of PD data that may be also contributed to the deficiency in the machine settings (which could add more strength and accurateness to our results). The use of MRI was expensive, time consuming and was a frightening experience to the patient (some patients refused to repeat the MRI in their follow up). In addition, many pitfalls were found in MRI techniques and lack of a standard protocol when performing MRI on such small parts as the hands and feet. Contrast MRI (or dynamic MRI) are more beneficial in detection of active joint inflammation than plain MRI (Østergaard et al., 2005 (a)). CONCLUSION MSUS is effective as MRI in early diagnosis of RA. It might be considered a good negative indicator of hand erosions. RECOMMENDATIONS Early clinical evaluation of arthritis using MSUS, as well as follow up, is highly recommended because of its accessibility, low cost and being considered a suitable bed side test more than MRI. Further work using the new 2010 ACR/EULAR criteria and avoiding all possible pitfalls of both imaging techniques is also recommended. 135

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