Stratification of biological therapies by pathobiology in biologic-naive patients with rheumatoid arthritis (STRAP and STRAP-EU): two parallel, open-label, biopsy-driven, randomised trials.

BACKGROUND: Despite highly effective targeted therapies for rheumatoid arthritis, about 40% of patients respond poorly, and predictive biomarkers for treatment choices are lacking. We did a biopsy-driven trial to compare the response to rituximab, etanercept, and tocilizumab in biologic-naive patients with rheumatoid arthritis stratified for synovial B cell status. METHODS: STRAP and STRAP-EU were two parallel, open-label, biopsy-driven, stratified, randomised, phase 3 trials done across 26 university centres in the UK and Europe. Biologic-naive patients aged 18 years or older with rheumatoid arthritis based on American College of Rheumatology (ACR)-European League Against Rheumatism classification criteria and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) were included. Following ultrasound-guided synovial biopsy, patients were classified as B cell poor or B cell rich according to synovial B cell signatures and randomly assigned (1:1:1) to intravenous rituximab (1000 mg at week 0 and week 2), subcutaneous tocilizumab (162 mg per week), or subcutaneous etanercept (50 mg per week). The primary outcome was the 16-week ACR20 response in the B cell-poor, intention-to-treat population (defined as all randomly assigned patients), with data pooled from the two trials, comparing etanercept and tocilizumab (grouped) versus rituximab. Safety was assessed in all patients who received at least one dose of study drug. These trials are registered with the EU Clinical Trials Register, 2014-003529-16 (STRAP) and 2017-004079-30 (STRAP-EU). FINDINGS: Between June 8, 2015, and July 4, 2019, 226 patients were randomly assigned to etanercept (n=73), tocilizumab (n=74), and rituximab (n=79). Three patients (one in each group) were excluded after randomisation because they received parenteral steroids in the 4 weeks before recruitment. 168 (75%) of 223 patients in the intention-to-treat population were women and 170 (76%) were White. In the B cell-poor population, ACR20 response at 16 weeks (primary endpoint) showed no significant differences between etanercept and tocilizumab grouped together and rituximab (46 [60%] of 77 patients vs 26 [59%] of 44; odds ratio 1·02 [95% CI 0·47-2·17], p=0·97). No differences were observed for adverse events, including serious adverse events, which occurred in six (6%) of 102 patients in the rituximab group, nine (6%) of 108 patients in the etanercept group, and three (4%) of 73 patients in the tocilizumab group (p=0·53). INTERPRETATION: In this biologic-naive population of patients with rheumatoid arthrtitis, the dichotomic classification into synovial B cell poor versus rich did not predict treatment response to B cell depletion with rituximab compared with alternative treatment strategies. However, the lack of response to rituximab in patients with a pauci-immune pathotype and the higher risk of structural damage progression in B cell-rich patients treated with rituximab warrant further investigations into the ability of synovial tissue analyses to inform disease pathogenesis and treatment response. FUNDING: UK Medical Research Council and Versus Arthritis.

Tocilizumab for the treatment of giant cell arteritis in Scotland: a report on behalf of the Scottish Society for Rheumatology standards subgroup.

Objectives: The aim was to describe a modern National Health Service (NHS) Scotland cohort of patients with GCA over 12 months of care to include clinical presentation, practices relating to assessment and treatment, and specifically, the use of tocilizumab. Methods: A multicentre audit of patients newly diagnosed with GCA between November 2019 and October 2021 was established on behalf of the Scottish Society for Rheumatology. Clinical data were collected retrospectively by rheumatology teams at participating NHS centres using electronic patient records. An extended cohort of patients from NHS Lothian was examined to investigate outcomes of tocilizumab use for >1 year. Results: Sixty-three patients from three NHS Scotland health boards were included, with analysis of data from 216 clinic episodes. Mean follow-up was 371 days. Mean age was 71 years; 62% were female. The most common presenting features were headache (93.6%), scalp tenderness (82.5%) and ocular symptoms (24%). At baseline, 63% of patients had at least one existing risk factor for adverse outcomes from high-dose CS use, namely hypertension (57.1%), diabetes (24%) and osteoporosis (11%). Thirty per cent of all patients (19 of 63) received tocilizumab, with only 11% (7 of 63) receiving tocilizumab owing to glucocorticoid risk factors at baseline. One-quarter of all patients (16 of 63) experienced relapse of GCA during follow-up, of whom six were subsequently treated with tocilizumab. Conclusion: This multicentre audit demonstrates that despite its availability for patients with risk factors for CS adversity and those who suffer relapse of GCA, tocilizumab is used in less than one-quarter of patients who might benefit. The reasons for this require further exploration.

Scottish rheumatology sonography course: five-year experience of delivering a mentorship-model rheumatology ultrasound training programme accredited by the consortium for the accreditation of sonographic education.

BACKGROUND AND AIMS: Ultrasound training for rheumatology practice in the UK is variable. Currently, there is no agreed minimum standard for training in ultrasound applied to rheumatology patient management. We present our experiences of implementing a competency driven ultrasound training, focused on hands and feet. METHODS AND RESULTS: The Rheumatology Sonography Course (RSC) was developed by the Scottish Rheumatology Ultrasound Group in collaboration with Glasgow Caledonian University. The RSC is delivered via a blended learning approach and includes training workshops, mentorship and clinical competency assessments. Mentors are supported and developed within their role. 31 trainees have enrolled on the course between 2014 and 2019. To date, 22 (71%) have completed. Change of job role was the main factor leading to non-completion. Thirteen mentors have supported the training and assessment of RSC trainees. All trainees reported positively that ultrasound training via the RSC model fulfilled their learning needs. CONCLUSION: The RSC is a feasible ultrasound training model for rheumatology practitioners. Whilst it provides a robust training framework, mentorship fees and university overheads increase the cost. The RSC provides motivation to mentors to train external trainees and supports the development of new ultrasound-based rheumatology services.

Efficacy and safety of subcutaneous tocilizumab in rheumatoid arthritis over 1 year: a UK real-world, open-label study.

OBJECTIVE: The ACT-MOVE study assessed the real-world efficacy and safety of s.c. tocilizumab (TCZ-SC), provided as monotherapy or in combination with conventional synthetic DMARDs (csDMARDs) over 1 year, in patients with RA and an inadequate response to csDMARD therapy and/or first TNF inhibitor. METHODS: In this UK multicentre, open-label phase IIIb study, patients received TCZ-SC 162 mg once weekly for 52 weeks as monotherapy or with csDMARDs. Efficacy and safety were evaluated at baseline, weeks 2 and 4 and every 4 weeks thereafter up to week 52. RESULTS: Of 161 patients who received at least one dose of TCZ-SC, 21 (13.0%) received TCZ-SC alone and 140 (87.0%) TCZ-SC with a csDMARD(s). From baseline to week 52, there was a mean decrease in DAS28-ESR score among all patients (-3.68), and within monotherapy (-3.75) and combination therapy (-3.67) groups. The proportion of patients who achieved DAS28 clinical remission (DAS28-ESR <2.6) at week 52 was 75.4% (95% CI 66.8, 82.8). At the same time point, ≥80% of patients who remained on TCZ-SC achieved DAS28 clinical remission or had low disease activity (DAS28-ESR ≥2.6 and ≤3.2). Overall, 6.2% of patients had at least one serious adverse event (10.2/100 patient-years), and there was one death; 11.2% of patients discontinued owing to adverse events. CONCLUSION: TCZ-SC was effective and tolerated in a real-world setting over 1 year. The efficacy of TCZ-SC was similar whether given as monotherapy or with csDMARDs; its safety profile was consistent with that previously established. TRIAL REGISTRATION: ClinicalTrials.gov, http://www.clinicaltrials.gov, NCT02046603.

The Scottish Early Rheumatoid Arthritis (SERA) Study: an inception cohort and biobank.

BACKGROUND: The Scottish Early Rheumatoid Arthritis (SERA) study is an inception cohort of rheumatoid (RA) and undifferentiated arthritis (UA) patients that aims to provide a contemporary description of phenotype and outcome and facilitate discovery of phenotypic and prognostic biomarkers METHODS: Demographic and clinical outcome data are collected from newly diagnosed RA/UA patients every 6 months from around Scotland. Health service utilization data is acquired from Information Services Division, NHS National Services Scotland. Plain radiographs of hands and feet are collected at baseline and 12 months. Additional samples of whole blood, plasma, serum and filtered urine are collected at baseline, 6 and 12 months RESULTS: Results are available for 1073 patients; at baseline, 76 % were classified as RA and 24 % as UA. Median time from onset to first review was 163 days (IQR97-323). Methotrexate was first-line DMARD for 75 % patients. Disease activity, functional ability and health-related quality of life improved significantly between baseline and 24 months, however the proportion in any employment fell (51 to 38 %, p = 0.0005). 24 % patients reported symptoms of anxiety and/or depression at baseline. 35/391 (9 %) patients exhibited rapid radiographic progression after 12 months. The SERA Biobank has accrued 60,612 samples CONCLUSIONS: In routine care, newly diagnosed RA/UA patients experience significant improvements in disease activity, functional ability and health-related quality of life but have high rates of psychiatric symptoms and declining employment rates. The co-existence of a multi-domain description of phenotype and a comprehensive biobank will facilitate multi-platform translational research to identify predictive markers of phenotype and prognosis.

Novel photoplethysmography cardiovascular assessments in patients with Raynaud's phenomenon and systemic sclerosis: a pilot study.

OBJECTIVE: Multisite photoplethysmography (PPG) cardiovascular assessments can evaluate endothelial, peripheral autonomic and arterial dysfunction. The aim of this pilot study was to investigate the potential clinical utility of the technology in assessing patients with SSc and primary RP (PRP). METHODS: Multisite PPG pulse measurements, a reference ankle brachial pressure index (ABPI) and a full clinical assessment were undertaken for three subject groups: SSc, PRP and controls. Endothelial and autonomic function and arterial disease measures were obtained using pulse wave analysis. RESULTS: Nineteen SSc, 19 PRP and 23 control subjects were assessed and compared. Endothelial function was significantly impaired in SSc (P < 0.02), but with no difference between controls and PRP. Receiver operating characteristic-based classification accuracy was 81% (sensitivity 90%, specificity 74%) for separating SSc from controls and 82% (sensitivity 84%, specificity 79%) for separating SSc from PRP. SSc patients with digital ulcers had significantly lower endothelial function compared with those without ulcers (P < 0.05). Autonomic dysfunction was suggested in both SSc and PRP and was most exaggerated in patients with diffuse SSc. All groups had overall normal ABPI and arterial stiffness timing measures. Bilateral timing differences at the toes, which represents peripheral occlusive arterial disease, did show increased asymmetry in SSc (P < 0.02). CONCLUSION: Multisite PPG pulse technology showed potential diagnostic ability. By using measures of endothelial function, it differentiated SSc from control and PRP subjects with an accuracy of at least 81%. Objective pulse-derived measures of autonomic function and arterial disease in SSc have also been reported in this pilot study.

Soft tissue swellings in the foot: rheumatoid nodulosis.

Background rheumatoid nodulosis is a rare disease characterised by multiple subcutaneous nodules, a high titre of rheumatoid factor, radiologically detectable cystic bone lesions, but with none or few of the systemic manifestations or joint activity of rheumatoid disease. Histopathologically, nodulosis is the same as the nodules found in rheumatoid arthritis. It is considered to be a benign variant of rheumatoid arthritis. A 69 year old male presents with multiple subcutaneous nodules on the feet. This case study highlights the benefits of ultrasound in establishing a correct diagnosis and management. Although rare, rheumatoid nodulosis is a consideration in the differential diagnoses of soft tissue swellings in the feet.