|Ahead of print publication
Ultrasonography of articular and periarticular structures as a relapse predictor in patients with clinically remitted rheumatoid arthritis
Mehdi Karami, Zohre Mohammadzadeh, Shadi Ebrahimian, Maryam Moradi, Sayedbonakdar Zahra
Department of Radiology, Medical School, Isfahan University of Medical Sciences, Isfahan, Iran
Department of Radiology, Isfahan University of Medical Sciences, Isfahan
Source of Support: None, Conflict of Interest: None
Introduction: Rheumatoid arthritis (RA) is an autoimmune disease causing mortality and morbidity among patients. The goal of RA treatment is remission and prevention of joint degeneration. Remission is diagnosed by physical examinations and laboratory markers. Due to the high rate of relapse, it appears that physical examination is not a sensitive method in detecting active and remitted RA patients. The aim of this study is to find whether ultrasonography (US) is an appropriate method in detecting active RA patients and estimating the relapse rate.
Methods: Seventy clinically remitted RA patients were enrolled based on the Disease Activity Score in 28 joints. They underwent US to examine the presence of synovitis, tendinitis, tenosynovitis, and bursitis and were followed for 6 months regarding the relapse rate. Moreover, the predictive value of US was measured. SPSS was used for analyzing data.
Results: According to the US findings, 27.1% of the clinically remitted patients had signs of active synovitis, whereas 15.7% of them showed signs of tenosynovitis, tendinitis, or bursitis. In addition, relapse was observed in 12.9% of the patients with clinical remission and was significantly higher in patients with signs of active synovitis (P < 0.05). The results also revealed that the prognostic values of US for estimating the relapse rate were 77.7% and 70.0% in terms of sensitivity and specificity, respectively.
Conclusions: US is capable of detecting active synovitis among patients with clinically remitted RA and also predicts those with a higher risk of relapse within 6 months. It is also useful in identifying people with active RA, whose clinical symptoms indicate remission of the disease. Involvement of periarticular structures including tenosynovitis, tendinitis, or bursitis cannot independently predict relapse in patients with RA.
Keywords: Arthritis, Doppler, rheumatoid, ultrasonography
|How to cite this URL:|
Karami M, Mohammadzadeh Z, Ebrahimian S, Moradi M, Zahra S. Ultrasonography of articular and periarticular structures as a relapse predictor in patients with clinically remitted rheumatoid arthritis. Indian J Rheumatol [Epub ahead of print] [cited 2020 Feb 22]. Available from: http://www.indianjrheumatol.com/preprintarticle.asp?id=274198
| Introduction|| |
Rheumatoid arthritis (nRA) is an autoimmune inflammatory disease which affects symmetric small and large synovial joints and results in pain, swelling, and stiffness that worsen following rest. Despite joint involvement, a systemic immune response causes periarticular manifestations including tendonitis and bursitis. Uncontrolled RA can cause erosion of cartilages and bones as well as destruction of joints and thus leads to major disabilities. One of the most important principles in slowing the disease progression is early diagnosis and treatment. Treatment starts in the active phase of the disease with the target of achieving remission. Joint damage and structural destruction are prevented by remission of the disease, while active RA can lead to major disabilities and joint degeneration. Some studies showed progressive joint damage despite clinical remission based on the current evaluation criteria, thereby reflecting low sensitivity of the mentioned method.,
Musculoskeletal ultrasonography (US) and magnetic resonance imaging are able to detect subclinical synovitis and erosions in joints with higher sensitivity than physical examination and clinical manifestations., Synovitis and joint inflammation are observed in grayscale (GS) US and synovial vascularity that are visualized by power Doppler (PD) and are important radiologic findings, reflecting signs of active disease.,, It is suggested that US is capable of detecting subclinical inflammations due to its higher accuracy than clinical remission criteria in detecting joint inflammation.
Despite the sensitivity of US, there exists controversy in the use of this method for evaluating and monitoring RA. The purpose of this study was to investigate the presence of joint inflammation, signs of arthritis, and involvement of periarticular structures in the US of remitted RA patients. It was also aimed to detect the rate of relapse rate within a 6-month period in order to confirm US as an appropriate alternative to clinical examination.
| Methods|| |
Seventy patients were included in this prospective study conducted from October 2018 to May 2019 in Rheumatology Clinic, Al-Zahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran. All patients fulfilled the 2010 American College of Rheumatology criteria and clinical remission criteria using the Disease Activity Score in 28 joints (DAS28), erythrocyte sedimentation rate, and C-reactive protein. The patients were examined by an expert rheumatologist. In this process, the ones with a history of radioactive synovectomy, joint surgery, traumatic arthritis, infectious arthritis, and crystalloid arthritis over the last year were excluded from the study.
The participants' demographic information including age, gender, medications, duration of the disease, and laboratory markers including rheumatoid factor (RF) and anticyclic citrullinated peptide (anti-CCP) were also collected.
The participants' informed consent was obtained, and the design of the study was approved by the institutional review board of the Radiology Department, ******, on August 9, 2017 (number 396542).
US was performed using two methods of high-resolution US and PD for 60 min within 24 h after clinical examination by two expert radiologists who were blind to the laboratory results and clinical examinations.
The US was done by an ALT HDI 3000 device having a linear array probe with a frequency ranging from 5 to 10 MHz in accordance with EULAR guidelines. The sonography assessments were based on B-mode or GS sonography and PD sonography., There was no change in the setting of the device during the study, and no software was upgraded.
Twenty-eight joints contained shoulders (2 joints), elbows (2 joints), wrists (2 joints), knees (2 joints), MCP (10 joints) and PIP (10 joints) were assessed by US bilaterally.
US was also performed on periarticular structures, including shoulder (long head of biceps tendon, supraspinatus tendon, infraspinatus bursa, subscapularis bursa, subdeltoid bursa and subacromial bursa), elbow (olecranon bursa and the site of flexor and extensor tendon junction to medial and lateral epicondyles, wrist (flexor carpi radialis tendon and flexor carpi ulnaris tendon), hip (trochanteric bursa), knee (anserine and prepatellar bursa), and ankle (extensor, flexor, and peroneal tendons).
The joints were examined regarding the presence of synovitis, tenosynovitis, tendinitis, and bursitis.
The presence of effusion, increased thickness of synovium, and/or synovial vascular velocity individually or collectively represented joint synovitis.
Tenosynovitis was defined as the detection of either fluid in the sheath and/or increased synovial thickness or both. Sonographic presentation of tendinitis was thickening of the tendon, decreased echogenicity, blurred margins, increased vascularity on color flow Doppler, and calcification in chronic tendinitis. Sonolucent, fluid-filled collection with poorly defined margins indicated the presence of acute bursitis.
RF and anti-CCP were measured using enzyme-linked immunosorbent assay.
The disease recurrence in the patients was examined within 6 months after clinical remission, and the relapse rate was recorded. In order to prevent the relapse secondary to therapy change or medication discontinuation, the treatment was continued using the same dosage during the follow-up period in patients who were in clinical remission. If the relapse was observed, it was removed to prevent major complications. During the follow-up period, the relapse was defined by an expert rheumatologist based on clinical and serological examinations.
The collected information on gender, age, duration of the disease, medications, RF, anti-CCP, the presence or absence of joint inflammation, and the disease recurrence were analyzed using SPSS software version 24 for Windows (SPSS Inc., Chicago, IL, USA). To this end, the frequency of the categorical variables as well as mean ± standard deviation (SD) of quantitative variables was concerned. The sensitivity and specificity of US were calculated using true positive/(true positive + false negative) and true negative/(true negative + false positive) formula, respectively. The Chi-squared test or Fisher's exact test was used to analyze the categorical variables. Logistic regression analyses were performed, and P < 0.05 was considered to be statistically significant.
| Results|| |
Seventy patients with clinically remitted RA including 15 (21.4%) males and 55 (78.6%) females were included in this study. The mean age of the participants was 52.91 ± 13.25 years ranging from 24 to 81 years. The mean ± SD duration of the disease was 11.42 ± 9.49 years with the minimum and maximum of 1 year and 40 years, respectively. Prednisolone was the most commonly used medication prescribed for 62 (88.6%) patients at dosage of 1–5 mg/day and with a mean dose of 3.1 mg/day. Among the 70 patients, 54 (77.1%) and 47 (67.1%) patients had methotrexate and hydroxychloroquine therapies, respectively. Furthermore, 9 (12.9%) patients used sulfasalazine and 2 (2.9%) participants used infliximab.
In this study, 47.1% of the patients were treated by a mixed therapy approach using prednisolone and two disease-modifying antirheumatic drugs (DMARDs). Prednisolone and one DMARD were prescribed for 40.0% of the patients, and 1.4% of the patients received prednisolone along with three or more DMARDs.
Moreover, forty individuals (57.1%) had a positive RF. The same result was obtained for anti-CCP. Positive serum RF or positive serum anti-CCP had no significant effect on the relapse of the disease or the presence of synovitis and tenosynovitis/tendinitis/bursitis (P > 0.05). The relapse rate was not significantly affected by age, gender, duration of the disease, positive RF, or positive anti-CCP (P > 0.05).
The US features suggested that 24 (34.3%) patients had sonographic features of active RA. Regarding the 24 individuals with positive US, synovitis was detected in 13 patients, tenosynovitis/tendinitis/bursitis was the only sonographic marker in 5 patients, and 6 patients had synovitis and tenosynovitis/tendinitis/bursitis at the same time. Synovitis was detected most frequently in the wrist (34.61%), knees (23.07%), and MCP (15.38%) [Table 1]. Of 19 patients with synovitis, monoarticular and oligoarticular involvements were observed in 8 (42.1%) and 11 (57.9%) patients, respectively. Subdeltoid bursitis was noticed in two patients, and one patient had symptoms of prepatellar bursitis.
|Table 1: Frequency of active synovitis in ultrasonography of different joints|
Click here to view
There was an excellent interobserver agreement in the reports on the ultrasonographic parameters (K = 0.93, P < 0.05).
During a 6-month follow-up period, the relapse of the disease was detected in nine (four males and five females) patients [Table 2], of whom seven patients had a positive US for synovitis and three patients had signs of both synovitis and periarticular involvement. None of the patients had periarthritis as a single sonographic finding. The prognostic values of US for estimating the relapse rate were 77.7% and 70.0% for sensitivity and specificity, respectively.
The comparison of the relapse rates in the patients with and without US findings revealed that the patients with joint inflammation, including synovitis, tenosynovitis, or bursitis, had significantly higher relapse rates than those with no sonographic feature of inflammation (P < 0.05). Tenosynovitis/tendinitis and bursitis involvement was not significantly different for the patients with and without the disease relapse; however, patients with relapse had significantly higher rate of synovitis (P < 0.05).
Binary logistic regression analysis was also used to detect the predictive value of synovitis for the relapse of the disease (P < 0.05, odds ratio = 14.29).
| Discussion|| |
In this study, 70 clinically remitted RA patients were examined using GS and PD US in terms of the presence of synovitis, tenosynovitis, tendinitis, and bursitis. The participants were followed up for 6 months in order to determine the relapse rate and verify the efficiency of this method in improving the assessment of disease activity and minimizing the relapse rate. We found that 77.7% of clinically remitted patients who experienced the relapse of the disease had sonographic findings suggesting synovitis at the beginning of the study. Regarding the 6-month follow-up period, it was found that the relapse of the disease was significantly correlated with the presence of joint inflammation, indicating that the ultrasound method can predict the recurrence probability based on the positive findings of active synovitis, tenosynovitis, tendinitis, and bursitis.
This study also showed that 34.3% of the clinically remitted RA patients were in the active phase of the disease base on US findings. This finding was consistent with previous data indicating that synovitis detectable by US is observed in most RA patients with clinical remission.,, It is also compatible with the evidence, implying that this method (history and clinical examination) is not necessarily correlated with the remission of RA, and it leads to an inaccurate diagnosis of true active RA. The DAS28 is a simple criterion to be calculated and is used in clinical practice. It shows the remission of RA if DAS28 <2.8; however, this method is not sensitive enough to detect the inflammation and progressive radiologic joint destructions in clinically remitted RA patients. Such a shortcoming has been reported in many studies even though there are increasing evidence supporting the validity of US in evaluating patients with active arthritis despite the negative sings of inflammation in the history and physical examinations.,, Higher sensitivity of US is reported in a study by Naredo et al. Moreover, Rezaei et al.'s study also confirmed the great diagnostic value of US in detecting inflammation and early inflammatory arthritis.
During the 6-month follow-up period, the higher relapse rate in patients with active arthritis detected by US than those with negative sonographic findings may suggest that therapeutic strategy should be based on ultrasonographic findings not on the basis of clinical examination and symptom improvement which might be secondary to the medication effect. In the TaSER study, it was reported that the ultrasound method as a regular assessment of RA disease activity led to a greater intensity of DMARD therapy; however, the researchers reported no statistically significant effect of the ultrasound on clinical, functional, health-related quality of life or imaging outcomes in patients. The role of US in the treatment decisions made in RA patients was also assessed in the ARCTIC trial. The results of this study demonstrate that, in comparison to the conventional tight control strategy, the ultrasound has no additional effect on disease activity, joint damage, physical function, joint swelling, and radiographic joint progression.
Although this study proposes US as a useful predictor of relapse, Haschka et al. reported anticitrullinated protein antibody positivity as a relapse predictor. In contrast, the results of the present study found no association between RA relapse and anti-CCP seropositivity.
In this study, we evaluated the prognostic value of periarthritis in the patients with active RA and found that no significant difference in the relapse rates of the two groups of patients with and without ultrasonographic evidence of periarthritis. This finding can show that the presence of periarthritis in US does not necessarily mean future relapse of the disease.
The presence of bursitis in the US of the RA patients was also reported in Karimzadeh et al.'s study. In their study, the most frequent involved bursa was prepatellar bursa. They suggested the presence of bursitis to be considered as a sign of the disease. In the present study, two patients had prepatellar bursitis and one patient was detected with subdeltoid bursitis.
There are some studies on the importance of periarticular structures of inflammation in the diagnosis of the RA. In their study, Boutry et al. found that ultrasound was more sensitive than physical examination in the diagnosis of periarthritis. This finding is consistent with findings of Herman et al., In a study on the shoulders of the patients with RA, common US abnormalities including rotator cuff tendon tears, effusion in the long head of the biceps tendon, and the involvement of subscapularis, supraspinatus, and infraspinatus tendons were reported. Karimzadeh et al. also reported that ultrasound is more accurate than physical examination in detecting periarthritis. There is, however, inadequate information on the RA relapse rate in individuals with observed periarthritis in US. On the other hand, tenosynovitis and bursitis are observed in early stages of the disease as such its proper management can prevent major complications. Due to the necessity of a proper medical management in these patients, further studies are recommended.
There are some limitations in this study. The relapse type and the length of remission before relapse were not specified. Moreover, the duration of RA in the patients varied from 1 to 40 years. To remove these limitations, more studies are needed to determine the efficacy of ultrasound in predicting the relapse in different patients with different relapse types, duration of the disease, and length of the remission before relapse occurrence.
| Conclusion|| |
Given the fact that the therapeutic strategy of RA depends on the flare-up and remission phases, the recognition of true remission of the disease is of particular importance and reduces the morbidity and mortality rates. Although this study reported the high sensitivity and specificity of US in detecting patients with subclinical RA, more studies with larger sample size are required to recommend US as a routine imaging method in patients with high risk of relapse.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Emery P. Rheumatoid arthritis: An overview. Pocket Reference to Early Rheumatoid Arthritis. UK: Springer; 2011. p. 16.
Kroot EJ, de Jong BA, van Leeuwen MA, Swinkels H, van den Hoogen FH, van't Hof M, et al.
The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis. Arthritis Rheum 2000;43:1831-5.
Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, et al.
2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) 2012;64:625-39.
Ben Abdelghani K, Miladi S, Souabni L, Kassab S, Chekili S, Laatar A, et al.
Role of ultrasound in assessing remission in rheumatoid arthritis. Diagn Interv Imaging 2015;96:3-10.
Felson DT, Smolen JS, Wells G, Zhang B, van Tuyl LH, Funovits J, et al.
American College of Rheumatology/European league against rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum 2011;63:573-86.
Mulherin D, Fitzgerald O, Bresnihan B. Clinical improvement and radiological deterioration in rheumatoid arthritis: Evidence that the pathogenesis of synovial inflammation and articular erosion may differ. Br J Rheumatol 1996;35:1263-8.
McGonagle D, Conaghan PG, O'Connor P, Gibbon W, Green M, Wakefield R, et al.
The relationship between synovitis and bone changes in early untreated rheumatoid arthritis: A controlled magnetic resonance imaging study. Arthritis Rheum 1999;42:1706-11.
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.
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;62:323-34.
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;54:3761-73.
Matsos M, Harish S, Zia P, Ho Y, Chow A, Ioannidis G, et al.
Ultrasound of the hands and feet for rheumatological disorders: Influence on clinical diagnostic confidence and patient management. Skeletal Radiol 2009;38:1049-54.
Naredo E, Bonilla G, Gamero F, Uson J, Carmona L, Laffon A. Assessment of inflammatory activity in rheumatoid arthritis: A comparative study of clinical evaluation with grey scale and power doppler ultrasonography. Ann Rheum Dis 2005;64:375-81.
Micu MC, Fodor D. Concepts in monitoring the treatment in rheumatoid arthritis- the role of musculoskeletal ultrasound. Part I: Synovitis. Med Ultrason 2015;17:367-76.
Filippucci E, Iagnocco A, Meenagh G, Riente L, Delle Sedie A, Bombardieri S, et al.
Ultrasound imaging for the rheumatologist VII. Ultrasound imaging in rheumatoid arthritis. Clin Exp Rheumatol 2007;25:5-10.
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.
De Lucia O, Ravagnani V, Pregnolato F, Hila A, Pontikaki I, Gattinara M, et al.
Baseline ultrasound examination as possible predictor of relapse in patients affected by juvenile idiopathic arthritis (JIA). Ann Rheum Dis 2018;77:1426-31.
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd
, et al.
2010 rheumatoid arthritis classification criteria: An American college of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62:2569-81.
Molenaar ET, Voskuyl AE, Dinant HJ, Bezemer PD, Boers M, Dijkmans BA. Progression of radiologic damage in patients with rheumatoid arthritis in clinical remission. Arthritis Rheum 2004;50:36-42.
Scirè CA, Montecucco C, Codullo V, Epis O, Todoerti M, Caporali R. Ultrasonographic evaluation of joint involvement in early rheumatoid arthritis in clinical remission: Power Doppler signal predicts short-term relapse. Rheumatology (Oxford) 2009;48:1092-7.
Saleem B, Brown AK, Keen H, Nizam S, Freeston J, Wakefield R, et al.
Should imaging be a component of rheumatoid arthritis remission criteria? A comparison between traditional and modified composite remission scores and imaging assessments. Ann Rheum Dis 2011;70:792-8.
Kawashiri SY, Suzuki T, Nakashima Y, Horai Y, Okada A, Iwamoto N, et al.
Ultrasonographic examination of rheumatoid arthritis patients who are free of physical synovitis: Power Doppler subclinical synovitis is associated with bone erosion. Rheumatology (Oxford) 2014;53:562-9.
Rezaei H, Torp-Pedersen S, Af Klint E, Backheden M, Kisten Y, Györi N, et al.
Diagnostic utility of musculoskeletal ultrasound in patients with suspected arthritis – a probabilistic approach. Arthritis Res Ther 2014;16:448.
Dale J, Stirling A, Zhang R, Purves D, Foley J, Sambrook M, et al.
Targeting ultrasound remission in early rheumatoid arthritis: The results of the TaSER study, A randomised clinical trial. Ann Rheum Dis 2016;75:1043-50.
Haavardsholm EA, Aga AB, Olsen IC, Lillegraven S, Hammer HB, Uhlig T, et al.
Ultrasound in management of rheumatoid arthritis: ARCTIC randomised controlled strategy trial. BMJ 2016;354:i4205.
Haschka J, Englbrecht M, Hueber AJ, Manger B, Kleyer A, Reiser M, et al.
Relapse rates in patients with rheumatoid arthritis in stable remission tapering or stopping antirheumatic therapy: Interim results from the prospective randomised controlled RETRO study. Ann Rheum Dis 2016;75:45-51.
Karimzadeh H, Seyedbonakdar Z, Mousavi M, Karami M. Comparison the percentage of detection of periarthritis in patients with rheumatoid arthritis using clinical examination or ultrasound methods. J Res Med Sci 2016;21:134. [Full text]
Hermann KG, Backhaus M, Schneider U, Labs K, Loreck D, Zühlsdorf S, et al.
Rheumatoid arthritis of the shoulder joint: Comparison of conventional radiography, ultrasound, and dynamic contrast-enhanced magnetic resonance imaging. Arthritis Rheum 2003;48:3338-49.
Boutry N, Morel M, Flipo RM, Demondion X, Cotten A. Early rheumatoid arthritis: A review of MRI and sonographic findings. AJR Am J Roentgenol 2007;189:1502-9.
Kim HA, Kim SH, Seo YI. Ultrasonographic findings of the shoulder in patients with rheumatoid arthritis and comparison with physical examination. J Korean Med Sci 2007;22:660-6.
[Table 1], [Table 2]