The recent arrival of biologic therapies such as anti–tumor necrosis factor (anti-TNF) agents for rheumatoid arthritis (RA) has presented an exciting opportunity for clinicians to aim for clinical remission at an early stage in the disease course. It has been shown, however, that even when early clinical remission is achieved, a given duration of treatment or duration of response is required to achieve sustained clinical remission after therapy withdrawal (1–3). This raises the suspicion that clinical remission is not an absence of inflammation (synovitis), but rather a low level of disease that is subject to both disease flare and progress, and is frequently detectable with imaging (4).
Previously, our group has demonstrated that true absence of imaging synovitis, as assessed by magnetic resonance imaging (MRI) and ultrasound (US) of the hand and wrist, is uncommon in patients with established RA who are deemed to be in clinical remission when receiving disease-modifying antirheumatic drug (DMARD) therapy (4). It was not known whether similar results would have been obtained in patients receiving combination-DMARD and biologic therapy. The results of such a scenario may provide a potential explanation for the need for sustained biologic therapy (rather than a short induction course of treatment) and for the differences in radiographic outcomes seen in clinical trials with biologics.
Histology may be the better method of studying remission, but it is limited by the number of joints that can be examined, and it cannot easily be used to monitor joints over time. MRI is a very sensitive tool for detecting inflammation but it is time consuming, can visualize only a relatively small anatomic area, and, due to cost and patient intolerance, is not ideal for monitoring multiple joints over many time points. In contrast, it has been shown that synovitis and vascularity can be accurately detected using gray-scale (GS) and power Doppler (PD) ultrasonography in the small and large joints of patients with RA (5), with good correlation with histology and MRI (6, 7). Additionally, as previously shown by our group, US is well tolerated and can image a large number of joints at multiple time points over a relatively short period of time, with good reproducibility data at the hand and wrist (4).
The aim of this prospective pilot study using US was to examine the longitudinal relationship between clinical remission and imaging remission with the hypothesis that it may be more appropriate to aim for persistent absence of imaging synovitis rather than clinical remission. Our specific objectives were to assess the amount of imaging synovitis present in patients with early RA receiving combination infliximab and methotrexate therapy, both during clinical remission and following achievement of clinical remission.
Patients and Methods
Successive patients with early RA (<12 months of symptoms) as defined by the 1987 American College of Rheumatology (formerly the American Rheumatism Association) criteria (8) were identified from the Leeds Early Arthritis Project. Approval was obtained from the local research ethics committee, and patients gave their informed consent prior to study participation. None of the patients had ever received DMARD or biologic treatments, and none had received corticosteroids during the preceding month. The patients received biologic therapy in the form of infliximab (3 mg/kg) and rapidly escalating methotrexate (up to 20 mg/week by infusion 3).
Clinical and functional assessments included the Disease Activity Score in 28 joints (DAS28) assessment, the Health Assessment Questionnaire (HAQ), and the Rheumatoid Arthritis Quality of Life (RAQoL) questionnaire. Laboratory tests for rheumatoid factor (RF) and C-reactive protein (CRP) level were performed at each infliximab infusion visit. Clinical remission was defined as a DAS28 score <2.6, and clinical response was defined as a decrease in DAS28 score of >1.2.
Ultrasound was undertaken using a Philips HDI 5000 (Phillips Medical Systems, Best, The Netherlands) employing either 12–5 or 13–7 MHz linear transducers. Scans were performed by a single experienced sonographer (RJW) on 42 joints (bilateral glenohumeral, elbows, wrists, metacarpophalangeal, proximal interphalangeal, knees, tibiotalar, midtarsal, and metatarsophalangeal [MTP]) just prior to infusions at 0, 2, 6, 14, 22, 30, 38, and 46 weeks. Individual joints were scored for synovitis using a semiquantitative scoring method on a 0–3 scale for both GS and PD. Scores were expressed per joint and as a total score (where all joint scores were added together to produce a total score for each visit). For the purpose of the study, absence of imaging synovitis was arbitrarily defined as both a total GS and PD score of 0.
Descriptive statistics were produced using SPSS for Windows, version 12.0.1 (SPSS, Chicago, IL). Spearman's rho test was used to produce correlation coefficients between baseline GS, PD, and DAS28 scores, time to clinical remission, and time spent in clinical remission.
Demographic and clinical data.
Ten patients were recruited with the following baseline demographic and clinical features: 5 women and 5 men, median age 52.5 years (range 21–78 years), median disease duration 6 months (range 3–11 months), 8 RF-positive, median CRP level 25 mg/liter (interquartile range [IQR] 11.53–69.25 mg/liter), median DAS28 score 6.02 (IQR 4.07–7.25), median raw HAQ score 13.5 (range 5.5–19.0), and median RAQoL score 18.5 (range 6.0–26.75). Of the 10 patients, 9 completed the study (1 patient died of a hemorrhagic cerebrovascular accident between infusions 6 and 7, which was felt to be unrelated to the study therapy).
At baseline, 280 joints were clinically examined, of which 123 (44%) were normal (nontender and nonswollen) and 157 (56%) were symptomatic; 76 (27%) were tender and 142 (51%) were swollen. By infusion 8 (week 46), 242 (96%) of the total 252 joints examined were clinically normal and 10 (4%) were symptomatic; 3 (1.2%) were tender and 7 (2.9%) were swollen.
Of the 416 joints examined using US, 264 (63.5%) had GS synovitis and 139 (33.4%) had PD synovitis. The most common joints with imaging synovitis were the wrist, hands, and feet, with the majority of those joints being scored grade 2 for both GS and PD. Of note, PD signal was uncommon in the MTP joints, except for the fifth joint. Total GS scores were higher than total PD scores in each patient; the median total GS value was 43 (IQR 35–50.5) and the median total PD value was 21 (IQR 13–35).
The number of joints with synovitis by GS and PD fell steadily until they began to plateau at 22 weeks, when 178 (48.9%) of 364 joints had GS synovitis and 23 (6.3%) of 365 joints had PD synovitis (Figure 1). However, low levels of imaging synovitis continued in several joints (Table 1).
Table 1. Summary of individual patient clinical responses and imaging scores*
The number of clinically normal joints at different time points with and without GS and PD synovitis is shown in Table 2. At baseline, 59 (48%) of the 123 clinically normal joints had evidence of GS synovitis and 27 (22%) had evidence of PD synovitis. At infusion 8 (week 46), 35.1% of clinically normal joints had evidence of GS synovitis and 6.6% had evidence of PD synovitis.
Table 2. Summary of semiquantitative ultrasound scores (GS and PD) in clinically normal joints at each infusion time point*
GS = gray-scale ultrasonography; PD = power Doppler ultrasonography.
Number of clinically normal joints.
Patients achieving clinical remission.
Of the 10 participating patients, 9 (90%) achieved clinical remission at a median infusion 4 (14 weeks). No patients in clinical remission had an absence of imaging synovitis; 190 (50.7%) out of 375 joints had GS synovitis and 57 (15.2%) had PD synovitis. In patients achieving clinical remission, the majority of abnormalities were scored as grade 1 (GS) and grade 2 (PD). The median total GS and PD scores at clinical remission were 25 (IQR 23–38) and 8 (IQR 4–10), respectively (Table 1).
There was a trend towards positive correlation between baseline DAS28 score and time to achieving clinical remission (r = 0.627, P = 0.071), and a negative correlation between baseline DAS28 score and time spent in clinical remission (r = −0.665, P = 0.036) once it was achieved. Neither GS nor PD scores were associated with the timing or duration of clinical remission. Correlation coefficients for the relationships between GS/PD and time to remission were r = −0.221 and r = −0.289, respectively.
To our knowledge, this study is the first to demonstrate the relationship between clinical and imaging remission in a prospective cohort of patients with early RA (who had received no previous treatment) receiving biologic therapy. From it, we draw 3 important conclusions. First, even when clinical remission was achieved with TNF blockade, the absence of imaging synovitis may not be achieved. This is consistent with our previous study of patients receiving DMARD therapy (4). Second, it was noted that once clinical remission was reached, imaging levels of synovitis continued to fall but later began to plateau, rarely returning to 0 within the study duration. Third, absence of imaging synovitis was not achieved with 12 months of therapy.
This study highlights the discrepancy between clinical examination and US. At baseline, 48% of clinically normal joints (nontender and nonswollen) had evidence of GS synovitis and 22% had evidence of PD synovitis. A potential criticism of this study centers on the fact that clinical remission can be achieved using the DAS28 despite the fact that patients may still have a number of tender and swollen joints. However, our results show the presence of imaging activity in a substantial number of clinically normal joints. The discrepancy between clinical and US findings was also demonstrated by the fact that at baseline, 11 (14.5%) of 76 tender joints and 35 (24.6%) of 142 swollen joints had no imaging synovitis (data not shown).
The strengths of this study include the fact that a large number of joints were scanned to give a total body synovitis score, which better reflects the overall disease load. We chose patients with early disease who were previously untreated because we felt that they were the ones whose conditions were most likely to be reversible, i.e., without fibrotic pannus and secondary degenerative joint disease. All patients were clinically assessed and scanned immediately prior to the infliximab infusion, when the effects of the previous infusion were likely to be lowest.
There were a number of limitations to this study. Most importantly, this was a small pilot cohort, which makes it difficult to extrapolate the results to a wider scale. The study had an open-label design that may have introduced an element of bias, but the sonographer was not aware of the clinical data. The average duration of scanning for each patient was 50 minutes per visit (including time for documentation), suggesting that this is not a feasible technique for routine clinical practice. Less frequent assessment or scanning a reduced number of joints (such as those suggested by Naredo et al ) would offer an adequate patient assessment.
This pilot study of patients with early RA, which aimed to explore the relationship between clinical remission and absence of imaging synovitis, demonstrates that even though clinical remission is achievable through early combination treatment with infliximab and methotrexate, true absence of imaging synovitis is not. This supports the concept that infliximab treatment should continue beyond the achievement of clinical remission, although it is still unknown whether we should be aiming for the absence of imaging synovitis as a treatment endpoint or whether, in fact, absence of imaging synovitis is unachievable. Further work on a larger scale is required to confirm these observations and to fully determine the clinical significance of low levels of imaging synovitis.
Dr. Emery had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study design. Wakefield, Quinn, Emery.
Acquisition of data. Wakefield, Freeston, Bryer.
Analysis and interpretation of data. Wakefield, Freeston, Emery.