The US7 score is an effective tool of monitoring in patients with rheumatoid arthritis over 6 months of Tocilizumab

Objectives: Musculoskeletal Ultrasonography (US) has increasingly been used as an outcome measure in clinical trials of RA. The German ultrasonography 7 (US7) score is a semiquantitative US scoring system that combined soft tissue changes (synovitis and tenosynovitis) and erosive bone lesions in seven preselected joints. We aimed to evaluate clinical and ultrasonographic evolution and their correlation in patients with rheumatoid arthritis (RA) treated with tocilizumab (TCZ) by using the German US7 score. Methods: Twenty-two consecutive patients, affected by RA [19 females, median age of 41 years (35, 50), median disease duration of 72 months (36,171)] who were none or partial responders to methotrexate were commenced on TCZ. The patients underwent clinical, laboratory, and ultrasonographic assessment at 3 visits (baseline and after 3 and 6 months). The Disease Activity Score in 28 joints (DAS28) was recorded at each visit. The German US7 score was performed to assess synovitis, tenosynovitis, erosions and synovial/tenosynovial vascularity. Clinical remission, defined by a DAS 28 < 2.6, was assessed at the 3 visits of follow-up. Results: At baseline, the median DAS28 score was 5.2 (4.4, 6.2) and the synovitis scores were 9.5 (6.7, 15) in GS ultrasound and 2.5 (0, 7.2) in PD ultrasound. After 6 months of therapy, the DAS28 significantly decreased to 1.6 (0.8, 2.4); p <0.001. GS and PD ultrasound scores significantly decreased respectively to 5 (4, 6); p=0.001 and to 0.5 (0, 1.7); p=0.04. Conclusion: The German US7 is effective to reflect the therapeutic response of RA patients under TCZ as same as clinical and biological findings. and functional status parameters changes and ultrasonographic findings variations 6 months after onset basing on the US7 score.


Introduction
Musculoskeletal ultrasound (US) is a valuable imaging tool in rheumatic diseases. It has become an imaging method that is routinely used in the daily practice of many rheumatologists for both disease activity assessment and therapy monitoring [1][2][3][4][5]. Moreover, Musculoskeletal US has increasingly been used as outcome measures in clinical trials of RA. The German ultrasonography 7 (US7) score is a semiquantitative US scoring system that combined soft tissue changes (synovitis and tenosynovitis) and erosive bone lesions in seven preselected joints. Tocilizumab (TCZ) is a humanized anti-interleukin 6 (anti-IL 6) receptor antibody that has been demonstrated in previous clinical trials to improve the signs and symptoms of RA and to prevent radiographic progression [6][7][8].
The objectives of the present follow-up study of RA patients treated with TCZ were to evaluate clinical and ultrasonographic evolution and to explore the correlation between clinical and functional status parameters changes and ultrasonographic findings variations 6 months after TCZ onset basing on the US7 score.

Material and methods Patients
Twenty-two consecutive patients (19 women and 3 men) who fulfilled the American College of Rheumatology 1987 revised criteria for RA [9] were included. The patients gave written consent according to the Declaration of Helsinki, and the study was approved by the local ethics committee.
The patients have a median age of 41 years (35, 50) and a median disease duration of 72 months (36,171). These patients who were non-responders or partial responders to methotrexate or having digestive intolerance to this Disease-Modifying Antirheumatic Drugs (DMARDs) were commenced on TCZ.
Each patient received intravenous injections of monotherapy (8 mg/kg intravenously every 4 weeks). The doses of the other drugs that each patient was taking were not changed during the study period. Patients had received stable doses of methotrexate for ≥8 weeks prior to study entry. Oral glucocorticosteroids (≤10 mg/day prednisone equivalent) and nonsteroidal anti-inflammatory drugs (NSAIDs) were permitted.

Clinical and laboratory assessment
Patients underwent clinical and laboratory assessment at 3 visits (baseline, 3 and 6 months after TCZ onset). Disease activity evaluation was performed by using the visual analog scales with values ranging from 0 to 100 mm for pain, patient and physician global assessments of disease activity. Functional status was assessed using the validated Moroccan version of the health assessment questionnaire (HAQ) [10]. Clinical assessment was determined by an independent physician experienced in the joint assessment.
Standard laboratory tests included erythrocyte sedimentation rate (ESR) determined by using the Westergren method and C-reactive protein (CRP) levels measured by using nephelometry. The Disease Activity Score in 28 joints (DAS28) was used to assess disease activity at each visit. Clinical remission was defined by a DAS 28 < 2.6 [11].

Ultrasonographic examination
US was performed with Toshiba Xario (SAA-660A) using a highfrequency 14 MHz linear array transducer with power Doppler unit. The US study was performed by two experienced rheumatologist sonographers (S.A and H.R) who were blinded to the clinical and laboratory findings in each patient. In addition, power Doppler (PD) was used with the following settings: PRF 0.7 KHz, gain 18-30 dB, low filter. The US was performed at the 3 visits (baseline, after 3 and 6 months).
The German US7 score was used to monitor RA activity. This 7-joint score by Backhaus et al. was evaluated in a longitudinal multicenter German study and found to reflect disease activity and therapeutic response [12]. The German US7 score is the first score that combines soft tissue changes such as synovitis and tenosynovitis as well as erosive bone lesions in a single US scoring system. This score includes an examination of the wrist, metacarpophalangeal (MCP) 2 and 3, proximal interphalangeal (PIP) 2 and 3, and metatarsophalangeal (MTP) 2 and 5 joints at the clinically dominant side with an assessment of synovitis, Paratenonitis /tenosynovitis and erosions [12].

Statistics
Statistical analysis was performed with SPSS statistical software, version 17.0 (SPSS, Chicago, IL). For quantitative parameters, we used the mean SD and range. RA activity, functional status, and US findings were compared between M0, M3 and M6 using ANOVA Variations of disease activity (ΔDAS28) and US7 scores (ΔGUS7) between M0 and M6 were achieved. The Pearson product-moment correlation was used to calculate the correlation between ΔDAS28 and ΔGUS7. P values less than 0.05 were considered statistically significant. Inter-and an intra-reader agreement was calculated using kappa coefficients between the readers. Responsiveness was visualized by use of simple error bar plots with 95% confidence interval. A mean kappa value of 0.85 was reached for the qualitative (yes/no) scoring of images by the 2 US readers. A mean kappa value of 0.74 was obtained for semiquantitative intra-reader testing of 5 images with signs of synovitis in GSUS, PDUS, and erosions. In addition, the interreader agreement was good: In the detection of erosions, kappa of 0.79 was achieved.

Discussion
The main goals for RA management are to control inflammation and slow or stop the progression of RA [13,14]. This study shows that both clinical and ultrasonographic parameters have been significantly improved in patients treated with TCZ. Significant improvement of disease activity was observed after 3 months of treatment by TCZ and was maintained at 6 months of follow-up. Beside disease activity, TCZ gets better functional status: HAQ improved significantly through follow-up. These results are in according to previous data.
Many clinical trials have verified the efficacy of TCZ for patients with RA [6][7][8][15][16][17]. A Cochrane database systematic review concluded that TCZ-treated patients taking concomitant methotrexate were four times more likely to achieve American College of Rheumatology (ACR) 50 improvement and 11 times more likely to achieve DAS remission than patients taking a placebo [6]. Results of recent real-life studies confirm the efficacy of TCZ for the treatment of RA in actual medical practice [17]. With the development of biological modifiers, a growing number of RA patients have been able to achieve remission [13][14]. Nearly two-thirds of our patients achieved remission 3 months after TCZ onset and keep into it.
Nowadays, nobody could contest that the US is a validated and reliable method for assessing joint inflammation [18][19][20]. Synovitis and effusion are detected by GS (B-mode) and pannus vascularization by use of PD [19]. Earlier data showed US sensitivity to change during treatment with biological medication [1][2][3][4][5].
Many scores are used to evaluate progression in activity and erosions in RA [21]. We have chosen German US7 to be used in US monitoring given that the validity of this score had already been demonstrated [12]. It is also a simple score since it is exploring fewer joints. Hammer and Kvien have already shown that this 7-joint score was as sensitive to change as the 78-joint score (larger and more complete US score) for B-mode and PD assessments [22]. Concerning synovitis and PD. What's extremely important in established rheumatoid arthritis is to monitor its activity in order to adapt adequately to the therapeutic scheme. In our patients treated with TCZ, synovitis and PD scores of the German US7 have improved significantly at M3 with persistent good results at M6.
Our US findings are in according to previously published literature. In preliminary data, Hama and al showed that PD ultrasonography is useful for assessing disease activity and predicting joint destruction in RA patients receiving TCZ [23]. In another study, Kamishima et. al, assessed disease activity in 26 RA patients in the first few months after starting TCZ treatment.
They found that quantitative value for PD signal in the finger joint was responsive and predictive of structural damage progression at 1 year [24].
Our patients suffered from RA with many months of evolution. Therefore, it was not surprising to observe that German US7 erosions score has not varied significantly during the study. Paratenonitis was absent in all US visits. This could be explained by the rarity of this type   of tendon involvement in RA. Paratenonitis is rather more observed in psoriasis arthritis patients [12].
Presence of positive correlations between clinical disease activity and German US7 score is also relevant for RA monitoring in medical practice.
In summary, our study assessed response to TCZ with a valid US score in a longitudinal design during TCZ treatment and showed both good clinical and US response to TCZ in RA patients.
Some limitations should be pointed out in our study. A limitation of our study is related to the trial being an open-label one, with neither the patients nor the physicians being blinded to the treatment regimen. To minimize this bias, the clinical and US assessments were performed completely independently of each other. Another weakness is the low number of participating patients. However, this number seems to be not negligible in the context of a developing country where access to biotherapy remains limited due to socioeconomic conditions [25,26]. However, despite the low number of patients included, the present study was able to detect significant improvements as well in the clinical as in the US scores.

Conclusion
This study suggests that patients with active RA treated with TCZ showed improvement of their DAS 28, HAQ and ultrasonographic parameters. The German US7 score is a valuable outcome measure of the response of small-joint synovitis and their activity to TCZ. These results should be verified by further studies.