Article Text

Very low prevalence of ultrasound-detected tenosynovial abnormalities in healthy subjects throughout the age range: OMERACT ultrasound minimal disease study
  1. Jeanette Trickey1,2,
  2. Ilfita Sahbudin1,2,
  3. Mads Ammitzbøll-Danielsen3,
  4. Irene Azzolin4,
  5. Carina Borst5,
  6. Alessandra Bortoluzzi6,
  7. George AW Bruyn7,8,
  8. Philippe Carron9,10,
  9. Coziana Ciurtin11,
  10. Georgios Filippou12,
  11. Jacek Fliciński13,
  12. Daniela Fodor14,
  13. Hélène Gouze15,
  14. Marwin Gutierrez16,17,
  15. Hilde Berner Hammer18,19,
  16. Ellen-Margrethe Hauge20,21,
  17. Annamaria Iagnocco22,
  18. Kei Ikeda23,
  19. Rositsa Karalilova24,
  20. Helen Isobel Keen25,
  21. Marion Kortekaas26,27,
  22. Giuliana La Paglia28,
  23. Gustavo Leon29,30,
  24. Peter Mandl31,
  25. Mihaela Maruseac32,
  26. Marcin Milchert13,
  27. Mohamed Atia Mortada33,
  28. Esperanza Naredo34,
  29. Sarah Ohrndorf35,
  30. Carlos Pineda36,
  31. Mads Nyhuus Bendix Rasch20,
  32. Cristina Reátegui-Sokolova36,37,
  33. Garifallia Sakellariou38,
  34. Teodora Serban39,
  35. Cesar A Sifuentes-Cantú40,41,
  36. Maria S Stoenoiu42,
  37. Takeshi Suzuki43,
  38. Lene Terslev3,
  39. Ilaria Tinazzi44,
  40. Florentin Ananu Vreju45,
  41. Ruth Wittoek10,46,
  42. Maria-Antonietta D'Agostino47,
  43. Andrew Filer1,2
  1. 1 Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK
  2. 2 NIHR Birmingham Biomedical Reserarch Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
  3. 3 Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen, Denmark
  4. 4 Academic Rheumatology Center, MFRU, Department of Clinical and Biological Science, University of Turin, Turin, Italy
  5. 5 Department of Dermatology, Medical University of Vienna, Vienna, Austria
  6. 6 Section of Rheumatology, Department of Medical Sciences, University of Ferrara and Azienda Ospedaliera-Universitaria di Ferrara, Cona, Italy
  7. 7 MC Hospital Group, Lelystad, Netherlands
  8. 8 Reumakliniek Flevoland, Lelystad, Netherlands
  9. 9 Department of Internal Medicine and Paediatrics, University Hospital Ghent, Ghent, Belgium
  10. 10 VIB Center for Inflammation Research, Ghent University, Ghent, Belgium
  11. 11 Centre for Adolescent Rheumatology, Division of Medicine, University College London, London, UK
  12. 12 University Hospital, Rheumatology Unit, ASST Fatebenefratelli Sacco, Milan, Italy
  13. 13 Department of Internal Medicine, Rheumatology, Diabetes, Geriatrics and Clinical Immunology, Pomeranian Medical University, Szczecin, Poland
  14. 14 2nd Internal Medicine, UMF Iuliu Haţieganu Cluj-Napoca, Cluj-Napoca, Romania
  15. 15 Hopital Ambroise-Pare, Boulogne-Billancourt, France
  16. 16 Clinica Reumatologica, Università Politecnica delle Marche, Ancona, Italy
  17. 17 Instituto Nacional de Rehabilitacion Luis Guillermo Ibarra Ibarra, Mexico, Mexico
  18. 18 Rheumatology, Diakonhjemmet Sykehus, Oslo, Norway
  19. 19 Faculty of Medicine, University of Oslo, Oslo, Norway
  20. 20 Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark
  21. 21 Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
  22. 22 Academic Rheumatology Centre, Università degli Studi di Torino, Turin, Italy
  23. 23 Department of Allergy and Clinical Immunology, Chiba University Hospital, Chiba, Japan
  24. 24 University Hospital Kaspela, Medical University of Plovdiv Hospital, Plovdiv, Bulgaria
  25. 25 Medicine and Pharmacology, UWA, Perth, WA, Australia
  26. 26 Leiden University Medical Center, Leiden, Netherlands
  27. 27 Flevoziekenhuis, Almere, Netherlands
  28. 28 Rheumatology Unit, Asst-Fbf-Sacco, Luigi Sacco Hospital, Milan, Italy
  29. 29 Instituto Nacional de Rehabilitacion, Mexico, Mexico
  30. 30 Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru
  31. 31 Department of Rheumatology, Medical University of Vienna, Vienna, Austria
  32. 32 Department of Rheumatology, Cliniques universitaires Saint-Luc, Brussels, Belgium
  33. 33 Department of Rheumatology Rehabilitation and Physical Medicine, Zagazig University, Zagazig, Egypt
  34. 34 Rheumatology, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
  35. 35 Department of Rheumatology and Clinical Immunology, Charité–Universitätsmedizin Berlin, Campus Mitte, Humboldt–Universität zu Berlin, Freie Universität Berlin, Berlin, Germany
  36. 36 Rheumatology, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico, Mexico
  37. 37 Universidad San Ignacio de Loyola, Lima, Peru
  38. 38 Istituti Clinici Scientifici Maugeri SpA SB IRCCS, Pavia, Italy
  39. 39 S.C. Reumatologia, ASL3 Genovese, Ospedale La Colletta, Genoa, Italy
  40. 40 Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
  41. 41 Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Tlalpan, Mexico
  42. 42 Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Rheumatology Department, Cliniques universitaires Saint-Luc, Brussels, Belgium
  43. 43 Division of Allergy and Rheumatology, Japanese Red Cross Medical Center, Shibuya, Japan
  44. 44 Unit of Rheumatology, IRCCS Ospedale Sacro Cuore Don Calabria, Negrar, Italy
  45. 45 Department of Rheumatology, University of Medicine and Pharmacy of Craiova, Craiova, Romania
  46. 46 Department of Internal Medicine and Paediatrics, Ghent University, Ghent, Belgium
  47. 47 Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
  1. Correspondence to Dr Andrew Filer, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK; a.filer{at}bham.ac.uk

Abstract

Objectives This study aimed to determine the prevalence of ultrasound-detected tendon abnormalities in healthy subjects (HS) across the age range.

Methods Adult HS (age 18–80 years) were recruited in 23 international Outcome Measures in Rheumatology ultrasound centres and were clinically assessed to exclude inflammatory diseases or overt osteoarthritis before undergoing a bilateral ultrasound examination of digit flexors (DFs) 1–5 and extensor carpi ulnaris (ECU) tendons to detect the presence of tenosynovial hypertrophy (TSH), tenosynovial power Doppler (TPD) and tenosynovial effusion (TEF), usually considered ultrasound signs of inflammatory diseases. A comparison cohort of patients with rheumatoid arthritis (RA) was taken from the Birmingham Early Arthritis early arthritis inception cohort.

Results 939 HS and 144 patients with RA were included. The majority of HS (85%) had grade 0 for TSH, TPD and TEF in all DF and ECU tendons examined. There was a statistically significant difference in the proportion of TSH and TPD involvement between HS and subjects with RA (HS vs RA p<0.001). In HS, there was no difference in the presence of ultrasound abnormalities between age groups.

Conclusions Ultrasound-detected TSH and TPD abnormalities are rare in HS and can be regarded as markers of active inflammatory disease, especially in newly presenting RA.

  • rheumatoid arthritis
  • ultrasonography
  • tendinopathy

Data availability statement

All data relevant to the study are included in the article or uploaded as supplemental information. Anonymised data are available on request from the authors.

https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

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Key messages

What is already known about this subject?

  • Little is known about the prevalence of sonographic tenosynovial abnormalities in healthy subjects (HS) across the age range.

What does this study add?

  • This is the largest cohort of healthy subjects with tendons scanned by ultrasound.

  • There is very low prevalence of tendon synovial hypertrophy or power Doppler abnormalities in tendons of HS even in old age.

  • Ultrasound-detected inflammation in digit flexor and extensor carpi ulnaris tendons in patients suspected to be in the early stages of rheumatoid arthritis (RA) should not be discounted as physiological, even in older age.

How might this impact on clinical practice or future developments?

  • Ultrasound-detected tenosynovial abnormalities can be regarded as robust findings in the clinical management of early RA.

Introduction

Tenosynovitis (TS) of hand and wrist tendons is common in early untreated inflammatory polyarthritis.1 However, clinical examination alone may not detect this pathology,2 especially as conventional rheumatoid arthritis (RA) disease activity scoring systems focus on joints, not tendons. The use of MRI and ultrasound examination is more sensitive and has shown that the prevalence of detecting TS in patients with early RA is higher than by physical examination alone.3

There has been extensive focus on the sensitivity and role of ultrasound in detecting subclinical synovial inflammation.4 5 Ultrasound has been shown to be highly sensitive in the detection of tenosynovial inflammation, with recent studies demonstrating that ultrasound-detected hand and wrist TS has a role in predicting outcome in early RA and flare in clinical remission.6 7

Although recent studies using MRI have focused on the prevalence of tendon abnormalities in healthy subjects (HS),8 there are limited data on the prevalence of ultrasound-detected ‘TS’ abnormalities in HS, with data arising from small comparison cohorts (ie, case–control studies focused on patients with rheumatic diseases). Furthermore, current studies were not focused on the prevalence of sonographic tendon abnormalities in HS within the age range of 40–70 years when RA commonly presents.9 The prevalence of such abnormalities therefore remains unknown in this group.

The objective of this Outcome Measures in Rheumatology (OMERACT) ultrasound study was therefore to determine the prevalence of ultrasound-detected tendon abnormalities characterising the presence of TS in HS according to the age range.

Methods

Adult HS (18–80 years) were recruited between August 2017 and December 2018 in 23 ultrasound centres in 14 countries with experience of participating in OMERACT ultrasound studies. To ensure a wide range of age coverage, recruitment was obtained from a large range of populations: university or hospital research staff, health service workers, students, volunteers from local advertising or national cohorts such as the Birmingham 1000 Elders group10 in the UK. Exclusion criteria were current or previous history of any form of inflammatory arthritis, joint trauma of hands or wrist in the previous month; hand or wrist pain of o≥10/100 on the Visual Analogue Scale; hand osteoarthritis according to American College of Rheumatology (ACR) criteria11; history of infection; and recent or current use of medications that may affect ultrasound assessment (see online supplemental table 1). An additional 12 HS were excluded after data collection but before ultrasound analysis due to autoimmune, infectious or musculoskeletal conditions identified from medical history that could confound the results. Demographic data including body mass index (BMI) were collected. Metacarpophalangeal, proximal interphalangeal, metatarsophalangeal and wrist joints were clinically examined by an independent assessor in each centre, and subjects were excluded if synovitis was found.

Ultrasound assessment of bilateral digit flexors (DFs) 1–5 and extensor carpi ulnaris (ECU) tendons was performed using a multiplanar approach. The presence of hypoechoic tenosynovial hypertrophy (TSH) and power Doppler signal within tenosynovial power Doppler (TPD) was defined and graded using the OMERACT ultrasound scoring system for TS in RA.12 The ungraded presence of tenosynovial effusion (TEF) was recorded. Adequate gel was used to avoid compression. Views were recorded according to European League Against Rheumatism (EULAR) standard reference scan guidelines.13 Musculoskeletal specific preset parameters were used to optimise imaging for greyscale and power Doppler and reduce variability. Details of probes, machines and experience of sonographers in all centres can be found in online supplemental table 2. Quality and grading of recorded images were confirmed by a review of all images for the first HS recruited in each centre by an experienced blinded independent assessor (IS) in the hub centre. Any disagreement was then fed back to the centre and consensus was achieved to ensure reliability in subsequent scans.

Data for a comparison cohort of DMARD-naive patients presenting as patients with new early arthritis with RA fulfilling ACR-EULAR 201014 and/or 1987 criteria15 at presentation were extracted from the Birmingham Early Arthritis (BEACON) inception cohort.6 The following data were collected: 68 tender and 66 swollen clinical counts, age, sex, symptom duration, early morning stiffness duration, medication, erythrocyte sedimentation rate (ESR), C reactive protein (CRP), rheumatoid factor and anti-citrullinated protein antibody status. This cohort underwent identical baseline tendon ultrasound assessment except for the presence of TEF.

Statistical analysis

Statistical analysis was performed using IBM SPSS Statistics V.26. Significance for the binary variable gender was assessed using Fisher’s exact test. The continuous variables age and BMI (for all subjects) and early morning stiffness, CRP and joint counts (for patients with RA) were not normally distributed; significance was therefore assessed using the Kruskal-Wallis test. The tendon gradings were dichotomised into either present (grades 1–3) or absent (grade 0). Fisher’s exact test was used to compare the proportions of grade 1–3 TSH, TPD or TEF between age groups in HS, and between HS and patients with RA.

Results

One thousand and forty-nine HS were recruited and 939 HS were included after exclusions of subjects with protocol deviations (see flowchart in online supplemental figure 1). Baseline data for 144 patients with RA were randomly extracted from the BEACON database and matched with a cohort of 144 HS by age, sex and smoking status where possible. Table 1 shows the demographic and ultrasound characteristics of the two populations. Full ultrasound grading results are available in online supplemental table 2 and example of grading in online supplemental figure 2.

Table 1

Demographics and tendon changes (grade 1–3 TSH and power Doppler) for HS and patients with RA

Healthy subjects

The median age of HS was 43 years (30–57). HS were grouped into three age groups: HS Y (young, 18–39 years) HS M (middle, 40–59 years) and HS O (old, 60–80 years) for analysis. The majority of volunteer HS were healthcare professionals (423, 45.0%). Other occupational groups included clerical staff (156, 16.6%), students (95, 10.1%), manual workers (68, 7.2%) and teachers (34, 3.6%).

A total of 11 237 tendons were scanned; 98% of these tendons were grade 0 for TSH, TPD and TEF (online supplemental table 3). The distribution of tendon abnormalities, when found, was symmetrical with no significant difference between right and left hands (online supplemental table 4). TEF was more frequently detected than TSH or TPD (p<0.001) (online supplemental table 5).

The majority (791/939, 84.2%) of HS presented grade 0 overall for all ultrasound lesions examined (TSH, TPD and TEF) in all DF 1–5 and ECU tendons. In particular 99% (931/939) of HS had grade 0 for TPD in all tendons scanned. There were no statistically significant differences between age groups (table 1 and figure 1).

Figure 1

Percentage of tendons with grade 1–3 TSH and TPD, and presence of TEF in DF tendons 1–5 and ECU for HS according to age groups, compared with patients with RA. TEF measured only in HS. HS Y, 18–39 years; HS M, 40–59 years; HS O, 60–80 years. DF, digit flexor; ECU, extensor carpi ulnaris tendon; HS, healthy subjects; M, middle; O, old; RA, rheumatoid arthritis; TEF, tenosynovial effusion; TPD, tenosynovial power Doppler; TSH, tenosynovial hypertrophy; Y, young.

Abnormalities were detected in 148 individuals across 939 HS and were of grade 1 severity, with the exception of one grade 2 for TSH in an ECU tendon. The ECU tendons had significantly more grade ≥1 for TSH than the DF 1–5 tendons (p<0.05) (online supplemental table 6).

There was no statistically significant difference in the proportion of TSH or TPD ≥1 in HS with manual professions, or in those who practice sports or hobbies which may have high impact on the upper limbs (online supplemental tables 7 and 8).

Patients with RA

Patients with RA were matched with 144 HS by age (within 2 years) and sex, and with smoking status in 116/144 HS. TS as defined by TSH and power Doppler grade ≥1 in DF and ECU tendons was more prevalent in patients with RA (52.8%) compared with HS (0.9%). There were significantly more TSH and TPD grade ≥1 detected in patients with RA compared with age-matched and sex-matched HS (p=0.002 to <0.001) (online supplemental table 9).

Discussion

Our study is the first to assess tendon involvement in large numbers of HS, encompassing the age incidence of RA with 367 HS over 50 years, and showing a very low prevalence of abnormal findings. The few abnormalities observed were almost exclusively grade 1 in severity. Due to the large population assessed, we provide conclusive data validating and expanding on the findings of existing studies with few HS.16–18

TEF was more prevalent than TSH or TPD in HS. Although MRI studies have suggested TEF to be almost ubiquitous in DF tendons in HS,19 we have shown that ultrasound detects smaller numbers: less than 2% of DF tendons even in the older age group. Visualisation of tendons in two dimensions is the most likely cause of this difference. Tenosynovial abnormalities on ultrasound were significantly more prevalent in early RA compared with matched HS.

By explicitly selecting only subjects with minimal joint pain and without overt osteoarthritis, and by using a non-random recruitment strategy to ensure inclusion of an older cohort, HS in this study may have fewer tendon changes than an unselected general population of 60–80 year olds. However, it was not our purpose to document the presence of tendon abnormalities in unselected primary or secondary care early arthritis clinics or in osteoarthritis, but to assess if HS with no symptoms may have ultrasound inflammatory abnormalities. The lack of a formal reliability study which would have been logistically difficult in such a large study, and the consecutive, not blinded recruitment may be seen as potential limitations. We mitigated these by designing a blinded central regrading strategy of the first HS scan performed by each centre.20

The very low prevalence of TSH and TPD across a large age range in HS suggests that these findings can be seen as potentially pathological, and not simply the consequence of ageing, by health professionals performing ultrasound in early arthritis or disease management clinics. The interpretation of such findings should depend on the clinical context. In addition, DF and ECU tendons can be easily examined during routine ultrasound examination and so could be included in abbreviated scanning protocols.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplemental information. Anonymised data are available on request from the authors.

Ethics statements

Patient consent for publication

Ethics approval

Ethical approval was obtained as appropriate in all participating centres according to each country's regulations, and written informed participant consent was obtained where necessary.

References

Supplementary materials

Footnotes

  • Handling editor Josef S Smolen

  • Twitter @PhilippeCarron, @A_Filer

  • JT and IS contributed equally.

  • M-AD and AF contributed equally.

  • Contributors JT and IS were equal contributors. MA-D and AF were equal contributors.

  • Funding The authors acknowledge the support of the National Institute for Health Research (NIHR) National Office for Clinical Research Infrastructure Translational Research Collaboration for Joint and Related Inflammatory Diseases and the support of their affiliated NIHR Biomedical Research Centres. We also acknowledge funding from the Versus Arthritis UK RACE collaboration between Glasgow, Birmingham and Newcastle Universities received by AF, and the Arthritis Therapy Acceleration Programme funded by the Kennedy Institute of Rheumatology.

  • Competing interests There are no declared competing interests from authors except the following: CC declared grants from NIHR Versus Arthritis, Lilly sponsored EULAR conference travel, Modern Biosciences payment as DSM committee member, Roche consultancy fee and Novartis sponsored writing of one medical paper. KI declared a Mitsubishi-Tanabe research grant for RA; Abbvie, Eli Lilly, Mitsubishi-Tanabe, Bristol-Myers-Squib and Novartis speaker’s fees; and participation on a DSM board for Abbvie, Eli Lilly and Mitsubishi-Tanabe. RK declared support from Abbvie, Roche, Novartis and UCB with payments for travel to meetings/lectures, presentations, speakers’ bureaus, manuscript writing/educational events.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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