Abstract
Background
In SLE, musculoskeletal manifestations have an impact on quality of life, disability and clinical trial outcomes, but are harder to assess than in RA and PsA. We previously showed ...that joint swelling lacks sensitivity, specificity and responsiveness compared to ultrasound. USEFUL was a multicentre longitudinal study to determine clinical features predicting ultrasound synovitis and whether patients with ultrasound synovitis respond better to therapy.
Methods
SLE patients were recruited if the referring physician deemed that they had inflammatory pain warranting treatment. Swollen joints were not required. At baseline, physicians recorded the features that led them to diagnose inflammatory pain and features of concurrent fibromyalgia and osteoarthritis. Stable doses of prednisolone (≤5mg/day), antimalarials or immunosuppressants were allowed. Participants received depomedrone 120mg IM then were assessed at 0, 2 and 6 weeks for 66/68 swollen and tender joint counts, BILAG-2004, SLEDAI-2K, physician global and MSK-VAS, inflammatory markers, patient pain and disease activity-VAS, HAQ-DI, LupusQoL, ultrasound of hands and wrists (blinded to patient and clinical assessor). An internal pilot determined the primary endpoint: EMS-VAS at 2 weeks (adjusted for baseline) between patients with ultrasound-synovitis vs. normal ultrasound at baseline. Sensitivity analyses adjusted for prednisolone and immunosuppressants.
Results
122/133 patients recruited completed all visits. There was significant disagreement between clinical examination and ultrasound. 78/133 had ultrasound synovitis; 68% of these had > =1 swollen joint. Of 66/133 patients with > = 1 swollen joint, 20% had normal ultrasound. Ultrasound-synovitis was more likely with joint swelling, a symmetrical small joint distribution and active serology. Physician-determined EMS, other lupus features or prior response to therapy were not associated. Fibromyalgia or osteoarthritis did not reduce the probability of ultrasound synovitis. In the full analysis set (n = 133) there was no difference in EMS VAS at 2 weeks according to ultrasound synovial status as baseline (difference -8mm, 95% CI -19, 4mm, p = 0.178). 32 patients had fibromyalgia. After excluding these patients, we found a statistically and clinically significantly better clinical response to depomedrone in patients with ultrasound-synovitis at baseline (baseline-adjusted EMS VAS at 2 weeks -12mm, 95% CI -24, 0mm, p = 0.049). This difference was greater in the treatment-adjusted sensitivity analysis (-12.8 (95% CI -22, -3mm), p = 0.007) and the per-protocol-adjusted sensitivity analysis (-14.8mm (95% CI -20.8, -8.8mm), p < 0.001). Patients with ultrasound synovitis had higher rates of improvement in the musculoskeletal BILAG-2004 (56% vs. 26%, p = 0.09) and SLEDAI-2K (37% vs. 15%, p = 0.03).
Conclusion
In lupus arthritis distribution and serology, but not other features, help identify ultrasound-synovitis. Ultrasound-synovitis was independent of features of fibromyalgia, but fibromyalgia confounded assessment of response. Excluding fibromyalgia, response to therapy was better in patients with abnormal ultrasound compared to normal. Ultrasound should be used to select patients for therapy and clinical trials, especially when there are inflammatory symptoms without swollen joints.
Disclosures
K. Mahmoud None. A. Zayat None. M. Md Yusof None. K.1. Dutton None. L. Teh None. C. Yee None. D. D'Cruz None. N. Ng None. D. Isenberg None. C. Ciurtin None. P. Conaghan None. P. Emery None. C. Edwards None. E. Hensor None. E.M. Vital Honoraria; AstraZeneca, GSK, Lilly.
Abstract
Objectives
This study aims to explore patients’ and clinicians’ experiences in managing and living with refractory disease (RD) and persistent physical and emotional symptoms (PPES) in ...patients with RA or polyarticular JIA from their perspectives through interviews and/or focus groups.
Methods
A qualitative exploration with 25 patients and 32 multidisciplinary rheumatology healthcare professionals (HCPs) was conducted to obtain participants respective understanding and experiences of managing RD/PPES and its impact on the patient–professional relationship. A pragmatic epistemology approach with framework analysis was employed.
Results
Four key themes were identified from both patients and professionals in the management of RD/PPES: risk/perpetuating factors/triggers; need for a patient-centred holistic approach to care, diagnosis and treatment; discordance and impact on the patient–practitioner relationship and current problems in managing RD/PPES. These themes covered 22 subthemes, with none being patient specific and seven being HCP specific. Suggestions for potential management strategies were highlighted throughout, such as involving other specialties or a multidisciplinary team, assessing/treating patient-reported outcome measures and psychosocial factors, patient (re)education, need for adjustments/aids or adaptations, checking the diagnosis and further investigations/imaging and optimizing medications.
Conclusion
Management strategies need to be developed that enable appropriate treatment plans for those with RD/PPES that account for wider biopsychosocial factors beyond inflammation and reduce discordance in the patient–practitioner relationship.
Lay Summary
What does this mean for patients?
Interviews with 25 people with either adult-onset or juvenile-onset arthritis and 32 rheumatology healthcare professionals (HCPs) were conducted and analysed to explore experiences in managing and living with refractory disease (not responding to medication) and persistent physical and psychological/emotional symptoms. Four key themes were identified: risk/ongoing factors/triggers; the need for a patient-centred approach to care, diagnosis and treatment; differences and impacts on the patient–HCP relationship and current problems with treatment. Suggestions for potential management strategies were highlighted, such as involving other HCPs or a multidisciplinary team (e.g. podiatry or physiotherapy), assessing/treating patient-reported outcome measures (e.g. self-assessment questionnaires), psychological (e.g. reducing disease-related distress) and social factors (e.g. peer support), patient (re)education (e.g. education and exercises for joints), need for adjustments/aids or adaptations, checking the current disease diagnosis, further investigations/imaging (e.g. additional blood tests or ultrasound) and optimizing medications (e.g. increasing dose or trialling previously used medications). This greater understanding of patient and wider healthcare team experiences can enable improvements in patient care to be made. Specialist clinics and conferences could be a starting point to discuss and agree upon appropriate management in conjunction with patients and enable sharing of best practices.
Abstract
Background
Biologic therapies have transformed the outlook for RA but the significant health economic impact of these therapies has highlighted the need to define predictive markers of ...response. Rituximab (RTX) is licensed for use following failure of csDMARDs and TNF inhibitor (TNFi) therapy. However, in this increasing therapeutically resistant cohort only 30% of patients achieve an ACR50 response. The observation in early RA that 50% of patients show low/absence of synovial B-cells prompted us to test the hypothesis that in these patients a biologic agent targeting alternative pathways maybe more effective. We report results from the first pathobiology-driven randomised controlled trial (RCT) in RA (R4RA) evaluating whether patient stratification according to the synovial B-cell rich/poor status enriches for response/non response to RTX.
Methods
R4RA is a phase IV open-label RCT conducted in 19 European centres recruiting patients failing or intolerant to csDMARD therapy and at least one TNFi. Synovial tissue was obtained at trial entry and used to classify patients as B-cell rich or poor using both histological and RNA-seq classification criteria. Patients were randomised to receive RTX or tocilizumab (TCZ). The study was powered to test in the B cell poor population superiority of TCZ over RTX at 16 weeks. The primary and co-primary end-points were defined respectively as Clinical Disease Activity Index (CDAI) ≥50% improvement from baseline and Major Treatment response (MTR)= CDAI improvement ≥ 50% and CDAI ≤10.1.
Results
The trial recruited to target (n = 164) with a power of 89.5%. In the B cell poor cohort a numerically higher number of patients achieved the primary endpoint and a significantly higher number of patients achieved co-primary endpoint (MTR). Classification of patients as B cell poor/rich according to RNA-seq criteria enhanced the difference between TCZ and RTX, with a significantly higher number of TCZ treated patients reaching both CDAI 50% improvement and CDAI MTR in the B-cell poor group.
Conclusion
In a RA B cell poor population failing csDMARDs and TNFi therapy, TCZ is more effective than RTX. This first biopsy-driven RCT suggests clinical utility for integrating molecular pathology profiling into treatment algorithms to allocate targeted therapies.
Primary and co-primary endpoints
Histological classification
RNA-seq classification
RTX
TCZ
p value
RTX
TCZ
p value
CDAI ≥50%
17/38 (44.7)
23/41 (56.1)
0.313
12/33 (36.4)
22/34 (64.7)
0.02*
MTR
9/38 (23.7)
19/41 (46.3)
0.035*
4/33 (12.1)
18/34 (52.9)
0.01*
*
denotes p value <0.05
Disclosures
F. Humby: Honoraria; Roche, Pfizer. Grants/research support; Pfizer. P. Durez: BMS,Bristol-Myers Squibb, Celltrion, Eli Lilly, Hospira, Mundipharma, Pfizer, Samsung, Sanofi, UCB. M. Buch: Consultancies; Pfizer, Roche, UCB, AbbVie, Eli Lilly, Sandoz, and Sanofi. Grants/research support; Pfizer, Roche, UCB, AbbVie, Eli Lilly, Sandoz, and Sanofi. M. Lewis: None. M. Bombardieri: None. H. Rizvi: None. S. Kelly: None. L. Fossati: None. R. Hands: None. G. Giorli: None. A. Mahto: None. C. Montecucco: None. B. Lauwerys: None. V.C. Romao: None. A.G. Pratt: Member of speakers’ bureau; Eli Lilly and Janssen-Cilag Ltd. Grants/research support; Pfizer. S. Bugatti: None. N. Ng: None. F. Rivellese: None. P. Ho: None. M. Bellan: None. P. Sainaghi: None. P. Verschueren: None. N. Gendi: None. B. Dasgupta: Abbvie, BMS, GSK, Roche, Roche Chugai, Sanofi, Sanofi Aventis, Sanofi-Aventis. A. Cauli: BMS, Celgene, Lilly, Lilly MSD, MSD, Novartis, Pfizer, Sanofi, Sigma Wesseumen, UCB. C. John: None. A. Nerviani: None. G. Thornborn: None. D. Holroyd: None. M. Congia: None. C. Thompson: None. P. Reynolds: None. J. Cañete: None. R. J. Moots: Biogen, Bristol-Myers Squibb, Chugai,
Novartis, Pfizer Inc, Roche, Sandoz, UCB. P.C. Taylor: AbbVie, Biogen, Celgene, Eli Lilly and Company, Fresenius, Fresenius SE & Co, Galapagos, Gilead. GlaxoSmithKline, Janssen, Lilly, Nordic Pharma, Pfizer, Pfizer Inc, Roche, Sanofi, UCB. C. Edwards: Abbvie, Biogen, BMS, Fresenius, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, UCB. J. Isaacs: None. P. Sasieni: None. J. E. Fonesca: None. E. Choy: AbbVie, Abbvie, Roche, Chugai, Amgen, Eli Lilly, Janssen, Novartis, Regeneron, R-Pharm and Sanofi, Amgen, Amgen, Roche, Chugai, Bristol-Myers Squibb, Eli-Lilly Janssen, Pfizer, Regeneron, Sanofi and UCB., AstraZeneca, Bio-Cancer, Bio-Cancer, Biogen, Novartis, Sanofi, Roche, Pfizer and UCB ,Biogen, BMS, Boehringer Ingelheim, Celgene, Chugai Pharma, Eli Lilly, Ferring Pharmaceuticals, GSK, Hospira, Janssen, Jazz Pharmaceuticals, Merck Sharp & Dohme, Merrimack Pharmaceutical, Napp, Novartis, Novimmune, ObsEva, Pfizer, Regeneron, Roche, R-Pharm, Sanofi, SynAct Pharma, Tonix, Union Chimique Belge. C. Pitzalis: None. NIHR have funded the study.
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.
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).
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).
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.
UK Medical Research Council and Versus Arthritis.
PDF
