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Musculoskeletal ultrasound using superb microvascular imaging documents treatment response to biosimilar infliximab in rheumatoid arthritis
  1. Julian Alejandro Santos1,
  2. Cherica Afurong Tee2,
  3. Romelito Jose Galvan Galsim1 and
  4. Michael Lucas Tee3,4
  1. 1Department of Radiology, Philippine General Hospital, Manila, Metro Manila, Philippines
  2. 2Division of Pediatric Rheumatology, Department of Pediatrics, Philippine General Hospital, Manila, Metro Manila, Philippines
  3. 3Department of Physiology, University of the Philippines Manila College of Medicine, Manila, Metro Manila, Philippines
  4. 4Division of Rheumatology, Department of Medicine, Philippine General Hospital, Manila, Metro Manila, Philippines
  1. Correspondence to Dr Michael Lucas Tee; mltee{at}up.edu.ph

Abstract

A 60-year-old woman with rheumatoid arthritis consulted for acute flare. She had elevated disease activity score 28 - erythrocyte sedimentation rate (DAS 28-ESR) of 6.88 and clinical disease activity index (CDAI) of 32. Her 12-joint ultrasound revealed widespread joint effusion. Synovial vascularity scores measured through superb microvascular imaging (SMI) and power Doppler were universally increased. We documented her treatment response 2 weeks after she received a single dose of biosimilar infliximab using clinical and sonographic data. Her DAS 28-ESR and CDAI scores decreased to 4.21 and 7.0, respectively. Reduction in synovial vascularity scores was demonstrated using SMI. While there was near total resolution in joint effusion and tenosynovitis, SMI was able to demonstrate synovial vascularity in joints with no clinical swelling nor tenderness. Musculoskeletal ultrasound and superb microvascular imaging are useful adjuncts in evaluating synovitis in rheumatoid arthritis and documenting treatment response through documentation of synovial vascularity, effusion and tenosynovitis.

  • radiology
  • rheumatoid arthritis
  • biological agents

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Background

Rheumatoid arthritis (RA) is the most common autoimmune inflammatory arthritis with a prevalence of 0.5% to 1%.1 It is characterised by chronic symmetric polyarthritis and can lead to debilitating joint damage and permanent disability, if left untreated.2

Early diagnosis, treatment and monitoring of disease activity can prevent or decelerate the development of joint damage and disability in majority of patients with RA.2 According to the American College of Rheumatology, musculoskeletal ultrasound can be used as an adjunct in the evaluation of inflammatory disease activity and structural damage, determination of alternate cause of inflammation, as well as monitoring of disease activity and structural progression.3 High-resolution grayscale (B-mode) ultrasound is used to identify synovial proliferation, as it can detect bone and cartilage erosions far better than plain radiographs. Doppler imaging is a valuable tool in demonstrating joint vascularity, active inflammation and neovascularisation.1 3 Superb microvascular imaging (SMI; Toshiba Medical Imaging, Canon Medical Systems, Otawara, Japan) is a new Doppler imaging technology that applies a multidimensional wall filter with an adaptive algorithm that identifies and removes clutter, a sonographic tissue motion artefact, while preserving visualisation of subtle low-velocity flow of tiny blood vessels in high detail.4 5

We report the SMI findings in a patient with RA following treatment with single dose of intravenous biosimilar infliximab. A 12-joint musculoskeletal ultrasound examination using grayscale, power Doppler imaging (PD) and SMI was performed before and after initial treatment.6 We documented evidence of joint inflammation and treatment response as detected by SMI and ultrasound and compared these with clinical disease activity indices. The case highlights the use of SMI in diagnosing and monitoring disease activity in patients with inflammatory arthritis.

Case presentation

A 60-year-old woman diagnosed with RA based on the 2010 ACR-EULAR (American College of Rheumatology/European League Against Rheumatism) classification criteria7 consulted at the outpatient clinic for acute arthritic flare. She had inadequate response to methotrexate (dose of 15 mg/week) and celecoxib. She presented with difficulty in ambulation and used a cane. On physical examination, she had tenderness on the left elbow and left first metacarpophalangeal (MCP) joints as well as on the right wrist, right second to fifth MCP and right knee joints. Swollen joints included the left shoulder, elbow and first MCP as well as the right wrist, right second to fifth MCP and right knee joints. There was a total of eight tender and nine swollen joints. The patient global assessment (PtGA) and provider global assessment (PrGA) of disease activity were likewise high at 8 and 7, respectively.

Initial investigations

Blood erythrocyte sedimentation rate (ESR) was markedly elevated at 118 mm/hour (reference range of 0–29 mm/hour for women). Using the aforementioned component ratings (eight tender joints, nine swollen joints, PtGA: 8, PrGA: 7 and ESR of 118 mm/hour), the pre-treatment disease indices were computed. The calculated Disease Activity Score 28 for ESR (DAS 28-ESR) was 6.88 and the clinical disease activity index (CDAI) was 32. Both scores indicated high disease activity.

Pre-treatment 12-joint ultrasound evaluation was performed on bilateral elbows, wrists, first and second MCP, knees and ankles by the principal author, and the findings were blindly-reviewed by the co-author who is a board-certified musculoskeletal radiologist. We took representative images from B-mode, power Doppler and SMI. A semiquantitative synovial vascularity scoring system was employed to standardise the evaluation of power Doppler and SMI findings. Grading ranges from 0 to 3, where grade 0 represents no colour in the synovium, grade 1 represents single or few small vessel signal, grade 2 represents confluent colour signals in less than 50% of the area of the imaged synovium and grade 3 represents extensive colour signals in more than 50% of the area of the imaged synovium.8

B-mode ultrasound revealed that, except for the right elbow which revealed no sonographic abnormality, nearly all the joints had varying degrees of synovial thickening and bony spurs. Synovial thickening and periarticular bone erosions were most severe in the bilateral first and second MCP joints as well as the wrists. Joint effusion was seen nearly universally, but was most severe in the MCP joints, left elbow and right knee. Approximately 30 cc of periarticular effusion was noted in the right suprapatellar bursa. Tenosynovitis was detected in the extensor compartments of the right wrist and the left flexor hallucis longus. SMI and power Doppler detected increased synovial vascularity in nearly all of the joints. Synovial hypervascularity was most severe in the hands and wrist and was generally more elevated in the joints of the right side of the body. (figure 1) SMI generally detected higher vascularity scores and in more joints when compared with PD. (figure 2) Total pre-treatment SMI synovitis score taken from all of the joints was 19 while total power Doppler synovitis score was 8. Table 1 summarises the pre-treatment ultrasound findings.

Figure 1

Representative pre-treatment power Doppler (PD) image of the right wrist. There is synovial hypertrophy and hypervascularity in the dorsum of the wrist.

Figure 2

Representative pretreatment superb microvascular image (SMI) of the right wrist. Notice the slightly more conspicuous linear vessels in SMI as compared with the power Doppler image.

Table 1

Summary and comparison of morphological B-mode ultrasound, power Doppler score and superb microvascular imaging findings before and after treatment

Treatment

The patient was given 200 mg biosimilar infliximab (Remsima, Celltrion), or 4 mg/kg. She was observed for 30 min after the treatment to monitor for allergic or infusion reactions. She was then sent home and asked to follow-up after 2 weeks. She was advised to continue her maintenance methotrexate and celecoxib. She was also instructed to return to the hospital if any symptoms of allergic reactions or infections occur.

Outcome and follow-up

On follow-up, 2 weeks after biological treatment, the patient reported improvement of both clinical and radiological parameters. She was able to ambulate without the use of the cane, enabling her to perform more daily tasks at home. Joint pain markedly diminished to 0–2/10 rating, predominantly experienced in the morning. Joint tenderness exhibited near total resolution, with residual in the right knee. Joint swelling also greatly decreased, observed only in the right second, third and fifth MCP joints. The PtGA and PrGA of disease activity drastically improved, rated at 1 and 2, respectively. Serum ESR was still elevated but decreased from 116 to 75 mm/hour. Using the aforementioned component ratings (one tender joint, three swollen joints, PtGA: 1, PrGA: 2 and ESR of 75 mm/hour), the post-treatment DAS 28-ESR score was 4.21 (moderate disease activity) and the CDAI score was 7.0 (low disease activity).

Post single-dose treatment 12-joint ultrasound with SMI and conventional power Doppler was performed as previously described. B-mode ultrasound showed widespread resolution in the tenosynovitis. Near total resolution of joint effusion was observed, with minimal residuals in the right suprapatellar bursa. Variable resolution of synovial hypertrophy was seen in some joints. There was no significant change in bony changes such as spurs and erosions. Universal reduction in post-treatment synovitis scores were observed. PD score decreased from 8 to 2 (figure 3) and SMI score decreased from 19 to 5 (figure 4). Table 1 summarises the pre-treatment and post-treatment ultrasound findings.

Figure 3

Representative post-treatment power Doppler (PD) image of the right wrist. Note the decreased Doppler signal when compared with the pre-treatment ultrasound.

Figure 4

Representative post-treatment superb microvascular image (SMI) of the right wrist. Similarly, there is decreased signal. However, SMI was able to show a low flow microvascular signal in the right wrist, despite no detectable abnormality during physical examination and power Doppler examination. (white arrow).

Discussion

The exact aetiology of RA remains unknown, but major histocompatibility complex gene mutations, smoking, Epstein-Barr virus infection, and Porphyromonas gingivalis periodontitis are noted associations. These factors promote activation of self-reactive T cells, which release proinflammatory cytokines such as tumour necrosis factor alpha (TNF-α) that mediate leucocyte and macrophage infiltration of the synovium. This leads to polyarticular synovitis, synovial proliferation (pannus) and neovascularisation. Progressive inflammation and pannus formation stimulate osteoclastic activity, resulting in periarticular osteopenia, bone erosions and articular cartilage destruction.1–3

This paper reports the case of a patient with elderly-onset RA who had insufficient response to adequate dose and duration of methotrexate. Having adequately satisfied the 2010 ACR-EULAR classification criteria and clinically ruling out differential diagnoses such as remitting seronegative symmetrical synovitis with pitting oedema, crystal arthritis and other connective tissue diseases, we proceeded to escalate treatment according to the 2019 update of the EULAR recommendations for the management of RA with synthetic and biological disease-modifying antirheumatic drugs.9 It should be noted that the decision to add a biological agent, specifically anti-TNF-α, was based on the current strategy of monitoring response to therapy that uses composite indices such as DAS-28 and CDAI which rely on clinical findings and laboratory data.

Indeed, despite several attempts, predicting response to biological treatment among patients with RA is currently not possible. Investigators have failed to consistently correlate demographic, biological parameters, as well as proteomic analysis with treatment response . Even the use of machine-learning approach failed to consistently predict outcome of treatment.10

This paper highlights the use of musculoskeletal ultrasound, particularly SMI, in documenting treatment response.

Rheumatoid synovitis or pannus manifests in gray scale (B-mode) ultrasound as synovial hypertrophy and is seen as hypoechoic or isoechoic thickening of the synovium with or without accompanying effusion. A radiologist can quantitatively evaluate the degree of synovitis by measuring synovial thickness or effusion volume. One limitation of gray scale ultrasound is that it cannot distinguish between chronic or active synovial inflammation because synovial thickening is retained over a period of time. Hypervascularity of the synovial membrane distinguishes acute from chronic inflammation. Power Doppler ultrasound is the present reference standard of care in assessing hypervascularity of the synovium.6 11 It uses the Doppler effect—a change in the frequency of reflected sound as it strikes a moving object. In medical sonography, this moving object is typified by flowing red blood cells.12 13 In actual sonographic examinations, Doppler signals are not only acquired from blood flow but also from tissue motion artefacts known as clutter. Conventional power Doppler imaging systems apply a single-dimension wall filter to remove clutter and motion artefacts, resulting to loss of signal from very low-velocity vessels.

SMI, on the other hand, applies a multidimensional wall filter with an adaptive algorithm that identifies and removes clutter while preserving visualisation of subtle low-velocity flow of tiny blood vessels in high detail.4 5 SMI was able to detect 18.5% more joint vascularity in patients with active RA and 60% more joint vascularity in subclinical RA. Semiquantitative synovial vascularity scores obtained using SMI also revealed greater correlation with serum inflammatory markers [CRP (C-reactive protein) and MMP-3 (matrix metalloproteinase-3)] and DAS 28-CRP scores as compared with semiquantitative scores taken using power Doppler.14 A systematic review by Gitto et al yielded six articles published between 2013 to 2019 dealing with the application of SMI in RA and other arthritides. A persistent finding is that SMI is more sensitive in detecting joint vascularity compared with power Doppler in both clinically active and inactive joints.15

To the knowledge of the investigators, this is the first reported case of SMI being used to document treatment response in a Filipino patient with RA, particularly to document response 2 weeks after a single dose of biosimilar infliximab. This case highlighted the usefulness of musculoskeletal ultrasound with SMI/power Doppler imaging as a clinical adjunct in evaluating synovitis in RA. Gray scale ultrasound documented evidences of treatment response, specifically decrease in joint effusion and tenosynovitis 2 weeks after a single dose of biosimilar infliximab. There was also corresponding decrease in the DAS 28 and CDAI scores. Variable resolution of synovial thickening was observed.

The SMI and conventional power Doppler demonstrated reduction in synovial vascularity after single treatment with biosimilar infliximab. SMI revealed subtle synovial microvascularity that was otherwise not visualised in conventional power Doppler, in this case, in the bilateral wrists. The presence of subclinical synovitis demonstrated by ultrasound can predict flare, relapse or disease progression even among patients with RA in clinical remission.16 Specifically, an elevated gray scale ultrasound-SMI synovial scores on specific joints were found to be associated with recurrence.17

There is a possibility that this subtle joint vascularity may account for the still elevated ESR of the patient after treatment. These same subtle microvascularity in the wrists detected through SMI were not evident clinically during the post-treatment physical examination carried out by the expert rheumatologist. This illustrates the possible use of SMI as an ancillary procedure for the evaluation and appropriate management of inflammatory arthritis such as RA. Further long-term, prospective studies that compare clinical and sonographic findings using SMI protocol is needed to determine the role of this modality in the overall treatment strategy for patients with inflammatory arthritis.

Patient’s perspective

“This disease (rheumatoid arthritis) has been debilitating for me and prevented my performing my daily tasks easily and effectively for almost a year now. I was informed that this disease rarely affects women of my age group, which made me more worried about my health in the years to come. The ultrasound examination done before and after my treatment allowed me to better understand what is going on with my body. It also gave me peace of mind by showing in real-time that the treatment I’m undergoing is working.”

Learning points

  • Musculoskeletal ultrasound is a useful adjunct in evaluating synovitis in rheumatoid arthritis.

  • Superb microvascular imaging (SMI) generally detected higher vascularity scores in more joints compared with power Doppler.

  • Ultrasound documents treatment response as reduction in synovial vascularity, effusion and tenosynovitis after successful treatment.

  • There was variable resolution of synovial hypertrophy after treatment.

  • SMI detects synovial vascularity not identified clinically nor by power Doppler protocol.

References

Footnotes

  • Twitter @raJULIgy_

  • Contributors JAS, MLT and CAT were involved in writing the manuscript. MLT performed the clinical evaluation and acquisition of clinical data. JAS and RJGG performed the ultrasound examination and review of images. The final manuscript was reviewed, edited and approved by the authors.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.