A Longitudinal Study of the 28 Joints of Disease Activity Score by Ultrasonographical Examination in Rheumatoid Arthritis Patients.

BACKGROUND: The damaging effect of rheumatoid arthritis (RA) on cartilage, bone, ligaments, and tendons has raised the importance of the disease activity and severity assessment to enable therapeutic decisions and to evaluate disease outcome. AIM: The aim is to compare the clinical examination of the Disease Activity Score (DAS)-28 with the musculoskeletal ultrasonography (US) examination in RA patients. Moreover, finding if we can use ultrasonographical results as a tool for predicting subsequent radiological damage. PATIENTS AND METHODS: It is a longitudinal study included 60 adult RA patients. Patients were under assessment at baseline, 6 months, and 12 months from the recruitment time. Twenty-eight joints of DAS were assessed for tenderness and swelling. US gray scale (GS) and US power Doppler (PD) score also was done at each visit.
RESULTS: DAS-28, with its parameters, is positively and highly significantly correlated to synovitis severity both by US GS and US-PD score along the study follow-up visits. There was highly significant difference between the number of 28 swollen and tender joints by clinical examination with both US GS and US-PD. Linear regression analysis to predict the number of swollen and tender joints after 12 months showed significance between US PD with swollen and tender joints' numbers. The correlation was positive and significant between Larsen score at 12 months with GS US and PD US assessment, but linear regression analysis was only significant for Larsen score with only GS US.
CONCLUSION: GS US and PD is a sensitive and reliable noninvasive method complementary to standard clinical assessment and could be a tool for predicting subsequent joints' damage.

INTRODUCTION

Rheumatoid arthritis (RA), with its characteristic synovitis which damages cartilage, bone, ligaments, and tendons, has raised the importance for the assessment of the disease activity and severity to enable therapeutic decisions and to evaluate disease outcome and response to treatment. In RA, structural damage is associated with pain and functional impairments.[1] Tender and swollen joint counts (SJCs) are essential features that should be examined during the routine clinical examination. The combination of joint counts and patients’ acute phase response, fatigue and pain scales, and stiffness are the measures to estimate disease activity.[2]

The measures were based on their sensitivity to change, their lack of redundancy, their content validity, whether they sampled multiple domains of RA activity, or whether they predicted important outcomes including disability, radiographic damage, and death. The American College of Rheumatology (ACR) criteria for remission,[3] the ACR improvement criteria,[4] and different continuous disease activity indices include these measures in various combinations.

The disease activity driven, or treat-to-target, treatment strategies need ideal measurement of disease activity. The most favorable measure for monitoring disease control is the DAS for 28 joints (DAS-28). The DAS-28 is a simplified form of its predecessor, the DAS.[5]

Early diagnosis of an aggressive course of synovitis or pannus is crucial for the basis of a decision for aggressive treatment. In the early phases of joint destruction, only a hypervascularized pannus can be detected.[6]

Clinical evaluation of joint pain and swelling has not been enough, and conventional plain radiography depicts indirect signs of cartilage loss and bony erosions.[7] Rheumatologists found that these DAS-28 scores had their limitations. Apart from disease activity, all individual component scores might be influenced by comorbidities,[8] joint counts can also be affected by a physician- and patient-related factors, and a patient's general health rating can be elevated because of noninflammatory or personal factors.[9]

Musculoskeletal ultrasonography (US) is a noninvasive and relatively inexpensive bedside imaging method with high patient acceptability.[10] Several studies have demonstrated that high-frequency US is accurate for detecting joint effusion.[111213] and synovitis.[14] Compared with magnetic resonance imaging[6] and direct arthroscopic visualization,[15] it has the advantage of the ability to examine all peripheral joints as many times as required at the time of consultation, which improves the accuracy of the clinical evaluation.

The US is a focus of attention since it has been proved to be more sensitive than clinical examination for synovitis detection. Moreover, in a study of patients with oligoarthritis, almost two-thirds of the patients had evidence of subclinical disease, and one-third could be reclassified as having polyarticular disease using US.[16] US can evaluate synovitis at the anatomic and vascular level. The B-mode gray scale (GS) setting enables the visualization of synovial hypertrophy and effusion, while the power Doppler (PD) setting allows the visualization of the movement of blood vessels, therefore detecting increased microvascular blood flow in synovitis.[10]

Aim of the work

We have two aims at this work; the first aim is comparing the number of inflamed joints detected by US with the number of tender and swollen joints detected by clinical examination, we used the 28 joints of DAS as the reference. The The second aim is testing if we can use ultrasonographical results as tools for predicting subsequent radiological damage.

PATIENTS AND METHODS

This study was carried out at the Department of Rheumatology and Rehabilitation, Sohag University hospital, during the period 2014–2016. The goals, steps, and methodology of the study were explained to the patients, and the consent forms were obtained. The study protocol was approved by the Ethics Committee of Sohag Faculty of Medicine, Egypt. The study is a longitudinal observational study included sixty adult RA patients, diagnosed according to the 2010 ACR/European League Against Rheumatism (EULAR) classification criteria; patients were under assessment at baseline, 6 months, and 12 months from the recruitment time. The included patient age at disease onset was after 16 years old. We have excluded from the study patients with other forms of connective tissue disease, osteoarthritis, trauma, and previous joint surgery.

The patients were under clinical, laboratory, and US evaluation at baseline, 6 months, and 12 months. The following data were recorded for each patient at study entry: age, sex, symptoms duration, morning stiffness, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids received for RA before study entry, disease-modifying antirheumatic drugs (DMARDs) prescribed, extra-articular involvement of RA, drugs received for RA. At each visit, 28 joints including bilateral glenohumeral, elbow, wrist, metacarpophalangeal (MCP), proximal interphalangeal (PIP) of the hands, and knee joints were assessed for tenderness and swelling. Tender joint count and SJC were recorded for each patient. A global pain intensity visual analog scale score (VAS pain; range 0–100 mm) and a VAS score for the patient's overall assessment of disease activity (range 0–100 mm) were recorded too.

Laboratory assessment

During each visit for the patients, they were under blood tests for C reactive protein (CRP) level, Erythrocyte Sedimentation Rate (ESR), Rheumatoid factor (measured by nephelometry), anti-Cyclic Citrullinated Peptide (anti CCP test), and complete blood count (CBC).

US assessment

Systematic GS and PD examination of the 28 joints was performed at each visit by a single rheumatologist experienced in US who was unaware of the clinical findings and he used; Ultrasonographic device model LOGIQ E, General Electric Medical Systems (GE healthcare), 12 USA, includes Multifrequency linear array transducers with frequency from 15 to 18 MHz US device.

GS synovitis scoring has been evaluated using a 4-Grade scale from 0 to 3 with the following subjective definitions for each category: Grade 0 = the absence of synovial thickening, Grade 1 = mild synovial thickening, Grade 2 = moderate synovial thickening, and Grade 3 = marked synovial thickening.

PD synovitis scoring using a 4-Grade scale from 0 to 3 with the following definition for each category: Grade 0 = absence of signal, no intra-articular flow, Grade 1 = mild, one or two vessels signal (including one confluent vessel) for small joints and two to three signals for large joints (including two confluent vessels); Grade 2 = moderate confluent vessels (>Grade 1) and < 50% of normal area; and Grade 3 = marked vessels’ signals in more than half the synovial area.

Joint synovitis was defined as the presence of intra-articular effusion and/or synovial hypertrophy.

Synovial blood flow was evaluated by PD in the hand joints. PD imaging was performed by selecting a region of interest that included the bony margins, articular space, and a variable view of surrounding tissues.

The conventional radiographic assessment used Larsen's scoring system[17] at the 12-month visit: plain X-ray was done for each patient and Larsen's score was calculated for each patient.

Statistical analysis

Data were recorded in Excel data sheet and analyzed using (Statistical Package for the Social Sciences software program version 24, IBM, Chicago, USA). Qualitative variables were recorded as frequencies and percentages and were compared by Chi-square test. Quantitative variables were presented as the mean ± standard deviation (SD) for normally distributed data and median with interquartile range for nonnormally distributed data and were compared by independent t-test. P < 0.05 was considered statistically significant.

RESULTS

The study included 60 Rheumatoid Arthritis patients, 56 are females (93.3%), and 4 are males, mean ± SD of age is 43.57 ± 10.51, the mean duration of symptoms was 4 years, with SD 1.3, and ranged from 1 to 7 years. Nearly 80% of the patients were RF positive and 83.3% of patients were anti-CCP positive at the recruitment time. The sixty patients completed the assessment at 6 months, while at 12 months, 6 patients missed the assessment due to unwilling to complete or traveling. The results of the comparison of the clinical and laboratory assessments between the three visits were; There was a significant difference between different times of follow-up regarding the acute phase reactants as a mean of both ESR and CRP decreased significantly from 0 month to 12 months with P = (0.004 and 0.009), respectively.

Furthermore, there was a significant difference regarding RF as 80% of patients had positive RF at 0 month and this percentage increased significantly to 86.6% after 6 months and 96.7% after 12 months. On the other hand, there was nonsignificant difference in Anti-CCP and CBC parameters (white blood cells [WBCs], platelets [PLTs], and hemoglobin [HB]); the other main assessments are displayed in Tables 1 and 2.

Table 1

Main assessment at follow-up periods

Variable	Present	At start 0 month 60 patients (%)	After 6 months 60 patients (%)	After 12 months 54 patients (%)	χ2	P
	Clinical
Morning stiffness	Yes	52 (86.7)	26 (43.3)	16 (30)	3.438	0.04 (S)
Extra-articular manifestations	Yes	4 (6.7)	4 (6.7)	6 (7.6)	30.000	0.002 (S)
	Treatment
NSAIDS	Yes	42 (70)	44 (73.3)	36 (66.7)	6.429	0.03 (S)
Steroids	Yes	30 (50)	30 (50)	34 (63.3)	0.133	0.715 (NS)
DMARDS	Yes	50 (83.3)	34 (90)	52 (96.7)	0.207	0.08 (NS)
Monotherapy	Yes	28 (46.7)	20 (33.3)	23 (43)	8.438	0.009 (S)
Combination therapy	Yes	22 (36.7)	34 (56.7)	29 (53.7)	8.294	0.007 (S)
	Acute phase reactant
ESR	Mean±SD	49.9±25.7	38.5±27.2	40±22.8	3.107**	0.004 (S)
CRP	Mean±SD	16.3±12.6	9.4±13	11±14.7	2.806**	0.009 (S)

McNemar Chi-square test was used to compare percentages of qualitative data, **Paired t-test was used to compare the means of quantitative data. NSAIDS: Nonsteroidal anti-inflammatory drugs, DMARDS: Disease-modifying antirheumatic drugs, ESR: Erythrocyte sedimentation rate, CRP: C-reactive protein, SD: Standard deviation, S: Significant, NS: Not significant

Table 2

Disease Activity Score 28 parameters and ultrasonography assessment at follow up periods

Variable	Mean±SD	Range	Paired t-test	P
Swollen joints
At start	7.17±2.60	1-12	4.218	<0.001 (HS)
6 months	5.57±2.90	1-12
12 months	5.23±3.23	0-12	3.471	0.002 (S)
Tender joints
At start	9.73±4.46	3-20	3.179	0.004 (S)
6 months	7.80±4.60	2-18
12 months	7.53±4.21	2-19	3.515	<0.001 (HS)
VAS
At start	58±18.64	30-90	5.277	<0.001 (HS)
6 months	40.67±20.16	10-90
12 months	39.67±22.51	10-90	4.097	<0.001 (HS)
DAS-28
At start	5.88±1.01	3.85-7.66	7.329	<0.001 (HS)
6 months	4.89±1.13	2.78-7.08
12 months	2.99±0.88	2.75-4.81	4.194	<0.001 (HS)
US gray scale score
At start	29±10.16	15-54	3.699	<0.001 (HS)
6 months	20.97±13.85	3-57
12 months	18.80±10.10	5-45	5.615	<0.001 (HS)
US gray scale number
At start	16.43±4.40	8-25	5.548	<0.001 (HS)
6 months	11.50±5.72	3-24
12 months	12.53±5.11	4-21	3.986	<0.001 (HS)
US PD score
At start	21.37±8.34	9-40	2.434	<0.001 (HS)
6 months	17.13±12.08	3-46
12 months	15.93±8.76	3-36	3.656	<0.001 (HS)
US PD joint number
At start	14.83±4.59	6-24	4.573	<0.001 (HS)
6 months	11.10±6.15	3-24
12 months	11.63±5.21	3-22	3.426	<0.001 (HS)

SD: Standard deviation, VAS: Visual analog scale, DAS: Disease Activity Score, US: Ultrasonography, PD: Power Doppler, S: Significant, HS: Highly significant

The Pearson correlation between the US GS score values and US PD score values with each of the ESR, CRP, and DAS28 at different follow-up periods was always positive with high significance (r > 0.56 and P < 0.001).

We did a comparison between the clinical examination and the US examination of the number of detected 28 swollen joints and tender joints and the results of comparison were highly significant with P < 0.001 at the three follow-up periods [Figures 1 and 2].

Figure 1

Comparison of swollen joints number with both US gray scale and US power Doppler at the three visits. At start of the study, mean and standard deviation of swollen joint count (7.17 ± 2.60), US-gray scale (16.43 ± 4.40) and of US-power Doppler (14.83 ± 4.59) with P = (0.001). At 6 months (mean and standard deviation of swollen joint count (5.57 ± 2.90), US-gray scale (11.50 ± 5.72) and of US-power Doppler (11.10 ± 6.15) with P = (0.001). At 12 months (mean and standard deviation of swollen joint count (5.23 ± 3.23), US-gray scale (12.53 ± 5.11) and of US-power Doppler (11.63 ± 5.21) with P = (0.001)

Figure 2

Comparison of tender joints’ number with both US gray scale and US Power Doppler at the three visits. At the start of the study, mean and standard deviation of Temasek Junior College (9.73 ± 4.46), US-gray scale (14.83 ± 4.59) and of US-power Doppler (16.43 ± 4.40) with P = (0.001). At 6 months (mean and standard deviation of Temasek Junior College (7.80 ± 4.60), US-gray scale (11.10 ± 6.15) and of US-power Doppler (11.50 ± 5.72) with P = (0.001). At 12 months (mean and standard deviation of Temasek Junior College (7.53 ± 4.21), US-gray scale (11.63 ± 5.21) and of US-power Doppler (12.53 ± 5.11) with P = (0.001)

The correlation between the number of detected inflamed joints by US (PD and GS) at 0 month of the study with the tender joints count at 12 months was positive and significant (r = 0.7, P = 0.04), but the correlation with the SJC at 12 months was positive and significant with only the US PD (r = 0.8, P = 0.03).

Linear regression analysis to predict the number of swollen and tender joints (after 12 months) from US GS to PD joint number at start showed significance between US PD joints number and swollen joints and tender joints [Tables 3 and 4].

Table 3

Linear regression analysis between swollen joints at 12 months and ultrasonography assessment at start month

Model	Unstandardized coefficients		Significant
	B	SE
Swollen joints at 12 months
Constant	0.722	1.860	0.701
US PD joint number	0.304	0.120	0.01 (S)
Swollen joints at 12 months
Constant	2.551	2.298	0.276
US gray scale number at start	0.163	0.135	0.237

SE: Standard error, US: Ultrasonography, PD: Power Doppler, S: Significant

Table 4

Linear regression between tender joints at 12 months and ultrasonography assessment at the start time

Model	Unstandardized coefficients		Significant
	B	SE
Tender joints at 12 months
Constant	0.660	2.321	0.778
US PD joint number	0.463	0.150	0.004 (S)
Tender joints at 12 months
Constant	0.853	2.712	0.756
US gray scale number at start	0.039	0.269	0.886

SE: Standard error, US: Ultrasonography, PD: Power Doppler, S: Significant

X-ray radiological changes still as one of the important parameters in the measuring of RA severity; in this study, we read the Larsen score for hands and feet at the 12 month assessment, and we did correlation between it and US assessment at 0 month of the study, which showed positive and significant correlation r = 0.67 and P < 0.05 with both PD and GS number, but linear regression analysis was only significant with GS US < 0.005. Correlation of Larsen score with the other disease parameters showed positive significance with the following: ESR (r = 0.7, P = 0.04), DAS 28 (r = 0.76, P = 0.001), and SJC (r = 0.6, P = 0.03).

DISCUSSION

In the early phases of joint destruction, only a hypervascularized pannus can be detected, early diagnosis of synovitis or pannus is essential for taking a decision of aggressive treatment. Many studies suggested improved sensitivity in the detection of synovitis, effusions within the joint, and bone erosions in rheumatoid joints using ultrasound (US) in comparison with traditional clinical examination and conventional radiography.[181920]

In this study, we worked for the 28 joints of DAS score as the most acceptable tool for measuring the diseases activity; we worked by two different ways for the assessment of these joints: the clinical examination of the tenderness and swelling of joints compared with the musculoskeletal US examination of the same joints, we wanted to find how sensitive is the US over the clinical in detecting the activity and severity of inflammation of these joints.

Our study included 60 adult patients fulfilling ACR/EULAR 2010 RA classification criteria, we followed them along 12 months: at baseline, 6 months, and 12 months. Follow-up was clinical (number of tender, swollen joints, and VAS), laboratory by CRP level, and ESR, CBC, DAS-28, and US examination by GS and PD the same hand joints.

Mean age of the patients was 43 years, with (SD 10.5), mean duration of symptoms was 4 years, with (SD 1.3), 87.6% of patients complained of morning stiffness at the first visit but the percent decreased to 43.3% after 6 months and became 30% after 12 months, and this difference was significant (P = 0.04) and may we can explain this change by the response to the treatment strategy of patients which adjusted at the follow up visits in order to decrease the disease activity. Only four patients in our study group had extra-articular manifestations at 0 month and still after 6 months. About treatment there was nonsignificant difference between the three visits in the steroids and disease-modifying antirheumatic drugs, but there was a significant difference in the NSAIDs, monotherapy, and combination therapy.

When we have done laboratory investigations to our patients, we found a significant difference along follow-up visits in the followings; acute phase reactants decreased significantly with the decrease in the disease activity, the percentage of RF-positive patients was significantly increasing. On the other hand, there was nonsignificant difference in CBC parameters (WBCs, PLTs, and HB).

Clinically, we found high significant difference through the three follow visits (0, 6, and 12 months) in the count of swollen joints, tender joints, VAS, and DAS-28 (P < 0.001) as a mean value of them decreased significantly from 0 to 12 months. This agreed with the results of Terslev et al.[21] as they showed good correlation between clinical improvement of the joint and decrease in DAS-28 in a longitudinal study.

By US examination, there was highly significant difference through the three follow-up visits (0, 6, and 12 months), US GS number, US PD score, and US PD joint number (P < 0.001) as a mean value of them decreased significantly. This was similar to the results of Elkhouly et al.[22]

The point, which we focused on in this study, is the differences between number of inflamed joints which were detected by clinical assessment and by US assessment and was significantly different, and this raises the value of US use in the assessment of disease activity, and directs our aim to be not satisfied with only clinical examination during monitoring of disease progression.

Consequently, these tools are of interest for monitoring RA patients in remission; we found that the baseline GS number and PD-US number can be used as predictive tool for number of swollen and tender joints after 12 months using linear regression analysis as follows:

Swollen joint = 0.722+ (US PD joint number at start × 0.304)

OR

= 2.551 + (US GS number at start × 0.163)

Tender joint = 0.660 + (US PD joint number × 0.463)

OR

= 0.853 + (US GS number at start × 0.039)

Dougados et al.[23] reported that the RA patients who were in disease remission or with low-level activity, baseline GS number, and PD-US number predicted relapse. Furthermore, several studies reported that the presence of subclinical synovitis by Doppler US is considered a predictive for radiographic progression in the future,[2425] Peluso et al. studied 96 patients with early and long-standing RA in stable clinical remission for at least 6 months (DAS < 0.6). US evaluation was on the second and third MCP, PIP joints, and the wrist of two hands. Of the negative PD (PD−) RA patients, 20% had a clinical flare during the 12-month follow-up period compared with 47% of positive PD (PD+) patients (P = 0.009), Scirè et al.[24] showed in 106 RA patients with clinical remission that a PD signal was a predictor for a future flare. In another one, the authors studied 93 patients with RA in clinical remission for 6 months and 26% of patients experienced a flare within the year; increased baseline PD activity was independently associated with the risk of flare.[26]

In our study, DAS was always positively and highly significantly correlated to disease severity both by US gray score and US PD score at any time during follow-up of our patients from start, after 6 months, and after 12 months. In a Swiss RA cohort, a significant but modest correlation between US (GS and PD score) and DAS-28 scoring was found.[27] Interestingly, when RA patients were prospectively evaluated, the same authors observed a positive association between GS (r = 0.41) and/or PD changes (r = 0.54) and change in DAS28.

We found also that ESR was always positively and highly significantly correlated to US GS and US PD score at any time during follow-up of our patients; CRP was also positively and highly significantly correlated to US GS and US PD score after 6 months and after 12 months, but it was nonsignificantly correlated to them at 0 month. Elkhouly et al.[22] found also a statistically significant correlation between ESR (P = 0.004) and GS US (P = 0.004). In a study of Ellegaard et al.,[28] PD was correlated with laboratory markers of inflammation, CRP, and ESR.

Garrigues et al.[29] concluded in their study that the concordance between clinical joint evaluation (CJE) and US was low at the MCP joints, wrists, and shoulders. Luukkainen et al.[30] also reported poor correlations between CJE and US at the MCP joints. Measurements in 37 patients with RA indicated a low correlation between the DAS-28 score and the 40-joint ultrasound score. This disparity calls into question use of the DAS-28 score as an assessment tool.[31]

In agreement, many studies have reported that subclinical synovitis can be detected by imaging of patients who have achieved clinical remission (DAS-28 < 2.6) after treatment, and such patients have a greater chance of bone erosion in the long run,[323334] we also found the significant correlation between the US joints examination at the baseline assessment with the radiological joint changes scored by Larsen at the 12-month visit.

CONCLUSION

We propose in this study that the use of musculoskeletal ultrasonographical examination could be a reliable method for improving the outcome of the standard clinical assessment in Rheumatoid synovial inflammation. We recommend the need to have more work in this point to raise the role of involving US joints assessment in RA within the disease activity score.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.