Ultrasound-detected subclinical inflammation was better reflected by the disease activity score (DAS-28) in patients with suspicion of inflammatory arthritis compared to established rheumatoid arthritis

We collected data from 276 consecutive patients referred to our rheumatologist-led US clinic to have a scan of their hand joints aiming to answer the clinician question about the presence of active inflammation in their joints. There were 108 patients with established RA, 93 were referred for the clinical suspicion of IA, 29 were previously diagnosed with psoriatic arthritis (PsA) and 46 patients had other diagnoses, including crystal arthropathies, sarcoidosis, osteoarthritis and chronic pain. We analysed in parallel the characteristics of the two main groups of patients: the group of established RA (n = 108) and the group of patients referred with S-IA (n = 93) (Table 1). The assessment of the follow-up clinical letters of S-IA patients revealed that 50.5 % (n = 47) were ultimately diagnosed with a form of IA, out of which 76.5 % (n = 36) were diagnosed with RA, 12.7 % (n = 6) with undifferentiated IA and 10.6 % (n = 5) with psoriatic arthritis. The rest of the patients initially referred with the suspicion of IA (49.4 %) were subsequently diagnosed with non-specific arthralgia, chronic pain or hand osteoarthritis.

The patients in the RA group were treated with methotrexate (MTX) alone or in combination with other synthetic disease-modifying anti-rheumatic drugs (DMARDs) in 79.6 % (86/108), SSZ alone or in combination in 48.1 % (52/108) and HCQ alone or in combination in 58.3 % (58/108). In terms of biologic treatments, 24.07 % (26/108) were on etanercept, 12 % (13/108) on adalimumab, 0.018 % on certolizumab (2/108), 0.09 % on rituximab (10/108) and 0.055 % on tocilizumab (6/108). Out of 108 patients with established RA, 89 patients (82.4 %) were on combination therapy. The RA patients were on stable conventional and biologic DMARD medication for at least 1 month prior to the scan. A minority of patients (21/108 in the RA group and 9/93 in the S-IA group) were treated with additional NSAIDs, and one S-IA had oral steroids (Table 1). These patients were excluded from the further analysis that stratified them based on their disease activity.

The comparison between the RA and S-IA groups with regard of the demographic, clinical, laboratory and US features is summarised in Table 1. The median number of joints with PD activity was significantly higher in RA patients (0, interquartile range (IQR) = 2.25 vs. 0, IQR = 1, p = 0.03), as was the number of joints with erosions (p = 0.004) and the number of joints with joint effusions (1.5 vs. 0, p = 0.013). However, the percentage of patients having at least one joint with active inflammation, as assessed by the presence of PD signal, was not significantly different between the two groups (52/93, 55.9 % vs. 45/108, 41.6 %, p = 0.56). Tendon abnormalities (such as effusion and tendon sheet thickening) were more frequently observed in patients with RA vs. S-IA (14/108 vs. 3/93, p = 0.042). The number of clinically assessed swollen joints correlated poorly with the US-detected inflammation (as assessed by PD signal) in both groups of RA and S-IA patients (r = 0.27, p = 0.54 and r = 0.39, p = 0.72, respectively).

The majority of patients with S-IA and positive PD signal in at least one joint (n = 52) were subsequently diagnosed with a type of inflammatory arthritis (47/52, 90.3 %), out of which, 36 patients were diagnosed with RA (69.2 %). In five cases, the presence of PD was associated with osteophytes and they have been diagnosed with inflammatory OA. Out of 25.8 % of patients with S-IA who had positive RF at the time of the US scan (n = 24/93), 23 patients were subsequently diagnosed with RA (23/36, 63.3 %); similarly, a proportion of ACPA-positive S-IA patients were ulterior diagnosed with RA (18/36, 50 %).

Further analysis compared RA patients stratified based on the DAS-28 activity scores (Table 2), and similarly, Table 3 comprises data on the S-IA group (Table 3). As mentioned earlier, the patients on oral steroids and NSAIDs were excluded from this analysis, which reported data on 87 RA and 82 S-IA patients. As expected, the RA patients stratified based on their DAS-28 scores had statistically different ESR, TJC, SJC, GVAS and pain scores; however, they had similar US parameters assessing for active and chronic inflammatory changes (Table 2). In contrast, the analysis of patients with S-IA revealed that DAS-28 score stratification identified patients with different PD and SH grade 3 scores, CRP and ESR levels, as well as patients with different TJC, SJC, GVAS and pain scores (Table 3). In addition, the S-IA groups with low, moderate and active diseases had a larger proportion of patients with true active inflammation (based on PD signal) than the group classified as being in clinical remission (p = 0.01) (Table 3). The comparison between the patient groups with a similar disease activity revealed that patients with RA and moderate and high disease activities (DAS-28 = 3.2–5.1 and >5.1, respectively) were significantly different from S-IA patients with similar DAS-28 scores, as far as the disease duration, ACPA positivity and number of joints with erosions were concerned (Table 4). RA patients in remission (DAS-28 < 2.6) had significantly higher TJC, number of joints with active inflammation and erosions, and higher number of patients with subclinical inflammation than the S-IA patients classified as being in clinical remission (Table 4). We also assessed for correlations between PD signal and erosions in RA patients in all the disease activity groups, and there were no positive correlations (p = 0.06, p = 0.26, p = 0.49, p = 0.12 for the different DAS-28 score groups, and p = 0.38 for the whole RA group, respectively). Out of all clinical outcomes, only SJC correlated with the PD score and only in patients with RA (p = 0.03). The presence of erosions also correlated with the patient’s age and disease duration (p = 0.04 and p = 0.03, respectively).

Most importantly, the DAS-28 scores did not correlate significantly with the PD scores in the RA patients (p = 0.25, p = 0.87, p = 0.13, p = 0.22, respectively, for the remission, low, moderate and active diseases, respectively). However, in the S-IA group, DAS-28 scores above 5.1 correlated significantly with the PD score (p = 0.048).

The binominal model analysis evaluated the impact of several variables on the risk of having active joint inflammation assessed by the presence of PD. The most negative values suggested a lower risk for positive PD signal in correlation with a certain parameter. Table 5 summarises the marginal effects of different variables on the number of joints with PD at the US examination in S-IA, RA patients, and patients with other arthropathies (labelled as non S-IA and non-RA). For instance, the average PD scores of S-IA patients increased by 0.004856 units in our prediction model as a consequence of having a hsCRP level above rather than below 5 mg/l. Similarly, the average PD score of a patient diagnosed with RA and treated with tocilizumab decreased by 1.81 units as compared to an RA patient who is not treated with tocilizumab (in the context of similar clinical picture and laboratory results). The most striking finding was that RA patients treated with tocilizumab tended had a lower PD score on US examination than patients treated with other biologics or DMARDs, despite similar clinical and laboratory findings (Table 5). The presence of RF increased slightly the risk of positive PD score only in patients with S-IA, and ACPA was associated with higher risk of active disease in patients with established RA, but had less influence on the S-IA group. Out of all three clinical outcomes, TJC, SJC and GVAS, only the SJC correlated with an increased PD score and only in patients with RA. The effect of different variables on the risk for a higher PD score was close to a zero value in the case of treatment with MTX and etanercept. For example, our prediction model suggested that in this group, the RA patients treated with MTX or etanercept monotherapy had a similar risk of having active joint inflammation on US. In this particular case, all the outcome measures taken into consideration in the prediction model are more relevant than being treated with MTX rather than etanercept.

We also attempted a cluster analysis of patients with similar DAS-28 scores using the following variables: age at scan; duration of symptoms; CRP; ESR; SH grades 1, 2 and 3; PD; presence of osteophytes; erosions; TJC; and SJC and GVAS. Although there was no obvious clustering of patients based on their diagnosis, the analysis revealed five big clusters with a large jump in the levels of two consecutive nodes (Fig. 1). One large cluster, including a significant proportion of S-IA patients with DAS-28 >5.1 exhibited the smallest amount of dissimilarity, suggesting that further analysis of larger patient groups might help identify which parameters are best to predict patients’ tendency to cluster in a certain disease group. Figure 1 represents the dendogram.