|Ahead of print publication
Correlation of clinical disease activity score with ultrasound disease activity score in rheumatoid arthritis patients of Kashmir Valley
Muzafar Naik1, Shaariq Naqati2, Mohammed Farooq Mir3, Tariq Bhat1, Mohammad Rafi Mir2
1 Department of Internal Medicine, SKIMS Medical College, Srinagar, Jammu and Kashmir, India
2 Department of Internal Medicine, SKIMS, Srinagar, Jammu and Kashmir, India
3 Department of Radio Diagnosis and Imaging, SKIMS Medical College, Srinagar, Jammu and Kashmir, India
|Date of Submission||01-Feb-2022|
|Date of Acceptance||24-Jul-2022|
|Date of Web Publication||18-Aug-2022|
Mohammad Rafi Mir,
Department of Internal Medicine, SKIMS, Srinagar - 190 015, Jammu and Kashmir
Source of Support: None, Conflict of Interest: None
Background: Musculoskeletal ultrasound can aid in assessing disease activity and deciding to taper off disease-modifying antirheumatic drugs in patients of rheumatoid arthritis (RA). With this background, we conducted a study to compare Clinical Disease Activity Score 28 C-reactive protein (DAS28 CRP) with Ultrasound Disease Activity Score 28 CRP (USDAS28 CRP) and its correlation with disease parameters in RA patients.
Materials and Methods: Forty-eight RA patients were subjected to clinical and ultrasound assessment of disease activity after subjecting them to history, clinical, and laboratory investigations. The clinical assessment was done by DAS28 CRP and the US assessment was done by USDAS28 CRP score. The swollen joint count and the tender joint count were replaced by GSUS (grayscale ultrasound) score and power Doppler ultrasound score, respectively, in USDAS28 CRP score.
Results: The mean age of the patients was 46.31 ± 13.90 years, with a mean duration of illness being 98.3 months. Nineteen patients had inactive disease and 29 patients had active disease on clinical examination. Six out of 19 (31.6%) patients with the inactive disease on clinical assessment had activity (subclinical synovitis) on US assessment. Two out of 29 (6.89%) patients with the active disease on clinical assessment had inactive disease on US assessment. Patients with subclinical synovitis had a longer disease duration (154 ± 114.2 vs. 73.38 ± 54.9 months, P = 0.05) and higher erythrocyte sedimentation rate (28.5 vs. 15 mm/H, P = 0.017) as compared to RA patients with the inactive disease on US assessment. Correlations between clinical scales and ultrasound scales were good (Pearson's r = 0.832, P = 0.01).
Conclusion: US scoring for disease assessment is a plausible method to assess subclinical activity in RA patients with inactive disease.
Keywords: Disease Activity Score, grayscale ultrasound, power Doppler ultrasound, remission, rheumatoid arthritis
|How to cite this URL:|
Naik M, Naqati S, Mir MF, Bhat T, Mir MR. Correlation of clinical disease activity score with ultrasound disease activity score in rheumatoid arthritis patients of Kashmir Valley. Indian J Rheumatol [Epub ahead of print] [cited 2022 Oct 3]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=353989
| Introduction|| |
It is well established that in rheumatoid arthritis (RA), active disease leads to joint damage, functional disability, and impaired health status., An accurate estimate of disease activity is of paramount importance for effective therapy with judicious use of drugs that otherwise could impair functional capacity and lead to radiographic progression.,,, For more than three decades, disease activity has been gauged by using composite scores based on clinical and laboratory data. Disease Activity Score 28 (DAS28), Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) are used frequently. These indices suffer from a few pitfalls: first, clinical assessments are subjective; second, very high tender joint count and small changes in erythrocyte sedimentation rate (ESR) disproportionately affect the scores at the low end of the reference range; third, inter-observer variability has been documented in these scores; and fourth, the joint count is an indirect assessment of inflammation in a joint and it can hardly be regarded as an objective measure.,
Among the laboratory parameters, conventional radiography remained the mainstay for evaluation of RA patients initially; however, as it shows late signs of disease activity such as destruction of cartilage or bone, ultrasonography and magnetic resonance imaging (MRI) are preferred nowadays in RA in order to assess the earlier signs.,, Musculoskeletal ultrasound is being used increasingly to assess joint activity in arthritis, although it needs expertise, it is a useful imaging modality with high patient acceptability. From the physician's point of view, there are stronger reasons to rely more on ultrasound, as grayscale ultrasonography (GSUS) is more sensitive than clinical examination for detecting synovitis and conventional radiography for detecting bone erosions.,, In addition, ultrasound correlates better with histology and MRI of joints in RA as compared to clinical examination., In order to be relevant in the decision-making of disease management, ultrasound scoring systems are necessary to delineate the active and inactive disease. Ultrasound Disease Activity Score (USDAS) is the first attempt to create a composite index that includes US scoring of synovitis, instead of clinical scoring of the number of swollen and tender joints.
We performed this study to correlate clinical assessment with ultrasound assessment of disease activity in RA patients and to predict factors that determine disease activity (subclinical synovitis) on ultrasound in clinically inactive RA patients and vice versa.
| Materials and Methods|| |
We performed this study at the Departments of Internal Medicine and Radio Diagnosis and Imaging, Sher-i-Kashmir Institute of Medical Sciences (SKIMS) Srinagar/SKIMS–Medical College and Hospital Srinagar over a period of 2 years (August 2017–July 2019). An approval from the Ethical Committee was granted to conduct the study. Informed consent was taken from all patients included in the study. A total of 48 patients were included in the study. The sample comprised subjects diagnosed with RA using the American College of Rheumatology (ACR)/European League Against Rheumatism 2010 Criteria or 1987 Revised Classification Criteria who attended the Outpatient Department or were admitted to the Department of General Medicine. Complete medical history and physical examination was done and a uniform standard procedure was used to check for joint examination. Investigations relevant to RA patients were done.
The swollen joint count, tender joint count, patient global assessment, and laboratory parameters (C-reactive protein [CRP]) were used to calculate DAS CRP with remission as ≤2.6, low as >2.6 ≤3.2, moderate disease activity as >3.2 ≤5.1, and high disease activity as >5.1.
All patients underwent blinded power Doppler ultrasound (PDUS) and GSUS examination within 48 h of clinical assessment. USG was conducted on ALOKA PROSOUND 3500 using linear high-resolution 10–12 MHZ transducers. A PDUS examination of 22 joints and a GSUS examination for effusion/hypertrophy (E/H) of 28 joints were performed. US examiner was blinded to clinical findings. GSUS E/H was qualitatively graded as absent (0) or present (1) in the following joints: 5 metacarpophalangeal, 5 proximal interphalangeal, bilateral wrist, bilateral elbow, bilateral shoulder, and bilateral knee (with sum range 0–28).
PDUS was semi-quantitatively graded based on the method of Szkudlarek et al. PD semi-quantitative score was graded in the following 22 joints: 2 wrists, 10 MCP joints, and 10 metatarsophalangeal joints (sum range: 0–66).
GSUS score replaced swollen joint count and PDUS score was used in place of the tender joint count using the formula for US DAS as follows:
USDAS = 0.56√ (PD22) +0.28√ (E/H28) +0.70 ln (ESR) +0.014 (GH).
CRP replaced ESR in the calculation of USDAS CRP. Cutoffs for grading the disease activity for USDAS CRP were the same as for USDAS ESR with remission as ≤3.3, low disease activity as >3.3 to ≤3.7, moderate disease activity as >3.7 and ≤5, and high disease activity as >5.
The Statistical analysis was performed using IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. (Armonk, NY: IBM Corp.) 23 was used for data analysis. Normality of test was done by Shapiro–Wilk test. Median with interquartile range was calculated for anti-citrullinated peptide antibody (ACPA), duration of illness, ESR, and CRP as they were not normally distributed. Mean with standard deviation was calculated for age, DAS28, DAS CRP, SDAI, and CDAI. Nonparametric data between two groups were analyzed utilizing the Mann–Whitney U-test. Parametric data between two groups were analyzed utilizing a sample t-test. Nominal categorical data were compared using the Chi-square test or Fisher's exact test as appropriate. Correlation between continuous variables (Clinical Disease Activity Scores and USDASs) was done using Pearson correlation. In all of the analyses, P < 0.05 was considered statistically significant.
| Results|| |
Forty-eight patients were included in the study, with a mean age of 46.31 years and a mean duration of illness being 98.3 months [Table 1]. All patients had positive ACPA and rheumatoid factor (RF). We observed that according to DAS CRP, 22.9% of patients were in remission, 16.7% had low disease activity, 50% had moderate disease activity, and 10.4% had high disease activity. Patients in remission and those with low disease activity were grouped as inactive disease group, whereas patients with moderate and severe disease activity were grouped together into active disease group for statistical analysis. ESR-based scores were higher than CRP-based scores for overall, inactive, and active RA patients on clinical examination as well as on ultrasound assessment [Table 2]. The inactive disease was seen in 39.5% of RA patients and 60.5% had active disease according to DAS CRP [Table 3]. There was no significant difference between mean age, ACPA levels, and duration of illness between two groups; however, as expected, ESR and CRP levels were significantly higher in active group [Table 1].
|Table 1: Demographic, clinical, and laboratory characteristics of overall, inactive, and active rheumatoid arthritis patients included in the study|
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|Table 2: Clinical and Ultrasound Disease Activity Scores of rheumatoid arthritis patients|
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|Table 3: Ultrasound activity in clinically inactive versus active rheumatoid arthritis patients|
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Using USDAS CRP, 10.4%, 20.8%, 41.7%, and 27.1% were in remission, low disease, moderate disease, and high disease groups, respectively. USDAS group was also divided into active (moderate plus high disease) and inactive (remission plus low disease activity). Correlations between clinical scales and ultrasound scales were good (Pearson's r = 0.832, P = 0.01). In our RA patients who were inactive on clinical examination, 6 patients out of 19 (31.6%) had active disease on USDAS, whereas 2 out of 29 (6.89%) of patients with clinically active disease (moderate and high disease activity) had the inactive disease (remission and low disease activity) on USDAS [Table 3]. There was a significant difference in duration illness and higher ESR levels in patients with masked disease activity as compared with those who were inactive on ultrasound also [Table 4].
|Table 4: Demographic, clinical, and laboratory parameters of active versus inactive power Doppler ultrasound in clinically inactive rheumatoid arthritis patients|
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| Discussion|| |
We observed in our study that RA patients with the active disease on clinical assessment had a significant positive correlation with USDAS. Of the RA patients who had the active disease by clinical assessment, most (93.1%) had the active disease by ultrasound assessment. This is in agreement with a previous study by Kamel SR et al, who also observed similar clinical and ultrasound agreement in disease activity. Maheshwari et al. also reported a positive correlation between DAS28 and synovitis score in all RA patients with the active disease on clinical examination. However, in their study, only one patient belonging to the clinical remission group showed evidence of subclinical synovitis on ultrasound assessment. On the other hand, among the clinically inactive RA patients, one-thirds had active disease by ultrasound. However, the study by Kamel et al. depicted ultrasound and clinical scores to agree and no major discordance was noticed in clinical and ultrasound assessment of disease activity as was observed by Ramírez et al.
In their study, Ramírez et al. exclusively studied 55 RA patients who were in clinical remission and none had active disease, whereas Kamel et al. had studied RA patients with the majority having active disease.
De facto observations made by Ramírez et al. are in agreement with our observations, where they reported active synovitis on ultrasound assessment in 45.4% of RA patients in clinical remission. In our study, we found that one-third of inactive RA patients had the active disease as defined by USDAS. The slightly increased frequency reported by Ramírez et al. could be explained by the fact that they did not use any scoring system in ultrasound assessment rather they used individual joint activity based on a stringent definition of synovitis by ultrasound, with SH grade ≥2 plus PDUS signal as having active synovitis. In addition, patient global assessment and CRP were not included in determining the disease activity. Hence, they may have overestimated the disease activity.
Another study conducted by Saleem et al. found that one-half of their patients in clinical remission had active synovitis on PDUS. Similarly, Hirata et al. in their study reported ultrasound indicated synovitis in one-fifth of patients as compared to the tender joint count of 12.2% and swollen joint count of 14.7% on clinical examination which is representative of concordance of clinical examination and ultrasound synovitis in our clinically active RA patients. Baker et al. in their study found synovial grayscale abnormalities in 100% and synovial power Doppler abnormalities in one-fourth of patients on ultrasound assessment in RA patients in clinical remission; however, within the active RA group, significant associations were observed between swollen joint count and higher total synovial grayscale score. The variability of subclinical synovitis reported in these studies is due to the different combinations of joints used in ultrasound assessment and different criteria used for defining synovitis on ultrasound assessment.
In our study, we found that among RA patients who were inactive on clinical examination, patients with joint activity on PDUS had a longer disease duration as compared to patients without joint activity on PDUS. This suggests that in patients with long-standing RA, the clinical assessment may miss synovitis (active or chronic) and ultrasound is sensitive to detect.
None of the studies to the best of our knowledge have reported the association between duration and subclinical synovitis in patients with RA. We noticed a trend toward lower ACPA levels in those clinically inactive RA patients with US-defined subclinical arthritis, although not significant. “Furthermore, in our study, we found that clinically inactive RA patients with active synovitis had higher ESR levels compared to those with US inactive disease. Although other disease activity parameters (CRP, DAS28ESR/CRP) also showed a trend toward higher values, they were not significant statistically.”
Ramírez et al. also in their study found that RA patients in clinical remission with ultrasound-defined synovitis had higher DAS28 CRP in addition to increased levels of several angiogenic factors., In addition, they also found that there was no significant difference between the prevalence and titers of anti-cyclic citrullinated peptide and RF titers in patients with or without active synovitis which is in agreement with our observations.
The following are limitations of our study: small sample size, absence of concomitant MRI assessment of joints, and absence of treatment outcomes of subclinical rheumatoid arthritis. However, the results of our study throw more light on the active synovitis in inactive RA patients, as compared to inactive synovitis in active RA patients, with the consequence of introducing the concept of masked synovitis in RA patients.
| Conclusion|| |
One-third of patients with inactive RA had active synovitis on US assessment. The inactive RA patients with active synovitis on ultrasound had a longer duration of illness and higher ESR as compared to patients without synovitis. Ultrasound is an indispensable tool for assessment of disease activity more so in inactive patients of RA; however, further study is needed on a larger sample size focusing, especially on the management and follow-up of RA patients with subclinical/masked synovitis.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Molenaar ET, Voskuyl AE, Dijkmans BA. Functional disability in relation to radiological damage and disease activity in patients with rheumatoid arthritis in remission. J Rheumatol 2002;29:267-70.
Fuchs HA, Kaye JJ, Callahan LF, Nance EP, Pincus T. Evidence of significant radiographic damage in rheumatoid arthritis within the first 2 years of disease. J Rheumatol 1989;16:585-91.
Grigor C, Capell H, Stirling A, McMahon AD, Lock P, Vallance R, et al.
Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): A single-blind randomised controlled trial. Lancet 2004;364:263-9.
Finckh A, Liang MH, van Herckenrode CM, de Pablo P. Long-term impact of early treatment on radiographic progression in rheumatoid arthritis: A meta-analysis. Arthritis Rheum 2006;55:864-72.
Kyburz D, Gabay C, Michel BA, Finckh A;
Physicians of SCQM-RA. The long-term impact of early treatment of rheumatoid arthritis on radiographic progression: A population-based cohort study. Rheumatology (Oxford) 2011;50:1106-10.
Nell VP, Machold KP, Eberl G, Stamm TA, Uffmann M, Smolen JS. Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis. Rheumatology (Oxford) 2004;43:906-14.
Gardiner PV, Bell AL, Taggart AJ, Wright G, Kee F, Smyth A, et al.
A potential pitfall in the use of the Disease Activity Score (DAS28) as the main response criterion in treatment guidelines for patients with rheumatoid arthritis. Ann Rheum Dis 2005;64:506-7.
Hart LE, Tugwell P, Buchanan WW, Norman GR, Grace EM, Southwell D. Grading of tenderness as a source of interrater error in the Ritchie articular index. J Rheumatol 1985;12:716-7.
Sommer OJ, Kladosek A, Weiler V, Czembirek H, Boeck M, Stiskal M. Rheumatoid arthritis: A practical guide to state-of-the-art imaging, image interpretation, and clinical implications. Radiographics 2005;25:381-98.
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;43:2762-70.
Botar-Jid C, Bolboaca S, Fodor D, Bocsa C, Tamas MM, Micu M, et al.
Gray scale and power Doppler ultrasonography in evaluation of early rheumatoid arthritis. Med Ultrason 2010;12:300-5.
Smolen JS, Landewé R, Breedveld FC, Buch M, Burmester G, Dougados M, et al.
EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014;73:492-509.
Wakefield RJ, Green MJ, Marzo-Ortega H, Conaghan PG, Gibbon WW, McGonagle D, et al.
Should oligoarthritis be reclassified? Ultrasound reveals a high prevalence of subclinical disease. Ann Rheum Dis 2004;63:382-5.
Szkudlarek M, Klarlund M, Narvestad E, Court-Payen M, Strandberg C, Jensen KE, et al.
Ultrasonography of the metacarpophalangeal and proximal interphalangeal joints in rheumatoid arthritis: A comparison with magnetic resonance imaging, conventional radiography and clinical examination. Arthritis Res Ther 2006;8:R52.
Baillet A, Gaujoux-Viala C, Mouterde G, Pham T, Tebib J, Saraux A, et al.
Comparison of the efficacy of sonography, magnetic resonance imaging and conventional radiography for the detection of bone erosions in rheumatoid arthritis patients: A systematic review and meta-analysis. Rheumatology (Oxford) 2011;50:1137-47.
Rees JD, Pilcher J, Heron C, Kiely PD. A comparison of clinical vs. ultrasound determined synovitis in rheumatoid arthritis utilizing gray-scale, power Doppler and the intravenous microbubble contrast agent 'Sono-Vue'®. Rheumatology 2007;46:454-9.
Hoving JL, Buchbinder R, Hall S, Lawler G, Coombs P, McNealy S, et al.
A comparison of magnetic resonance imaging, sonography, and radiography of the hand in patients with early rheumatoid arthritis. J Rheumatol 2004;31:663-75.
Damjanov N, Radunovic G, Prodanovic S, Vukovic V, Milic V, Simic Pasalic K, et al.
Construct validity and reliability of ultrasound disease activity score in assessing joint inflammation in RA: Comparison with DAS-28. Rheumatology (Oxford) 2012;51:120-8.
Szkudlarek M, Court-Payen M, Jacobsen S, Klarlund M, Thomsen HS, Østergaard M. Interobserver agreement in ultrasonography of the finger and toe joints in rheumatoid arthritis. Arthritis Rheum 2003;48:955-62.
Kamel SR, Sadek HA, Mohamed FA, Osman HM. Role of ultrasound disease activity score in assessing inflammatory disease activity in rheumatoid arthritis patients. Egypt Rheumatol 2018;40:1-5.
Maheshwari S, Chatterjee S, Atal AT, Grewal DS, Vibhuti Maria V. The relationship between US7 ultrasound joint scoring system and disease activity score DAS28 in rheumatoid arthritis: A study in Indian population. Indian J Rheumatol 2019;14:290-6. [Full text]
Ramírez J, Ruíz-Esquide V, Pomés I, Celis R, Cuervo A, Hernández MV, et al
. Patients with rheumatoid arthritis in clinical remission and ultrasound-defined active synovitis exhibit higher disease activity and increased serum levels of angiogenic biomarkers. Arthritis Res Ther 2014;16:R5.
Saleem B, Brown AK, 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;60:1915-22.
Hirata A, Ogura T, Hayashi N, Takenaka S, Ito H, Mizushina K, et al.
Concordance of patient-reported joint symptoms, physician-examined arthritic signs, and ultrasound-detected synovitis in rheumatoid arthritis. Arthritis Care Res (Hoboken) 2017;69:801-6.
Baker KF, Thompson B, Lendrem DW, Scadeng A, Pratt AG, Isaacs JD. Lack of association between clinical and ultrasound measures of disease activity in rheumatoid arthritis remission. Ther Adv Musculoskelet Dis 2020;12:1-8.
Mandl P, Naredo E, Wakefield RJ, Conaghan PG, D'Agostino MA;
OMERACT Ultrasound Task Force. A systematic literature review analysis of ultrasound joint count and scoring systems to assess synovitis in rheumatoid arthritis according to the OMERACT filter. J Rheumatol 2011;38:2055-62.
[Table 1], [Table 2], [Table 3], [Table 4]