To unravel the hierarchy of cellular/molecular pathways in the disease tissue of early, treatment-naïve rheumatoid arthritis (RA) patients and determine their relationship with clinical phenotypes ...and treatment response/outcomes longitudinally.
144 consecutive treatment-naïve early RA patients (<12 months symptoms duration) underwent ultrasound-guided synovial biopsy before and 6 months after disease-modifying antirheumatic drug (DMARD) initiation. Synovial biopsies were analysed for cellular (immunohistology) and molecular (NanoString) characteristics and results compared with clinical and imaging outcomes. Differential gene expression analysis and logistic regression were applied to define variables correlating with treatment response and predicting radiographic progression.
Cellular and molecular analyses of synovial tissue demonstrated for the first time in early RA the presence of three pathology groups: (1)
dominated by the presence of B cells in addition to myeloid cells; (2)
with myeloid lineage predominance but poor in B cells nd (3)
characterised by scanty immune cells and prevalent stromal cells. Longitudinal correlation of molecular signatures demonstrated that elevation of myeloid- and lymphoid-associated gene expression strongly correlated with disease activity, acute phase reactants and DMARD response at 6 months. Furthermore, elevation of synovial lymphoid-associated genes correlated with autoantibody positivity and elevation of osteoclast-targeting genes predicting radiographic joint damage progression at 12 months. Patients with predominant pauci-immune pathology showed less severe disease activity and radiographic progression.
We demonstrate at disease presentation, prior to pathology modulation by therapy, the presence of specific cellular/molecular synovial signatures that delineate disease severity/progression and therapeutic response and may pave the way to more precise definition of RA taxonomy, therapeutic targeting and improved outcomes.
Although targeted biological treatments have transformed the outlook for patients with rheumatoid arthritis, 40% of patients show poor clinical response, which is mechanistically still unexplained. ...Because more than 50% of patients with rheumatoid arthritis have low or absent CD20 B cells—the target for rituximab—in the main disease tissue (joint synovium), we hypothesised that, in these patients, the IL-6 receptor inhibitor tocilizumab would be more effective. The aim of this trial was to compare the effect of tocilizumab with rituximab in patients with rheumatoid arthritis who had an inadequate response to anti-tumour necrosis factor (TNF) stratified for synovial B-cell status.
This study was a 48-week, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial (rituximab vs tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis; R4RA) done in 19 centres across five European countries (the UK, Belgium, Italy, Portugal, and Spain). Patients aged 18 years or older who fulfilled the 2010 American College of Rheumatology and European League Against Rheumatism classification criteria for rheumatoid arthritis and were eligible for treatment with rituximab therapy according to UK National Institute for Health and Care Excellence guidelines were eligible for inclusion in the trial. To inform balanced stratification, following a baseline synovial biopsy, patients were classified histologically as B-cell poor or rich. Patients were then randomly assigned (1:1) centrally in block sizes of six and four to receive two 1000 mg rituximab infusions at an interval of 2 weeks (rituximab group) or 8 mg/kg tocilizumab infusions at 4-week intervals (tocilizumab group). To enhance the accuracy of the stratification of B-cell poor and B-cell rich patients, baseline synovial biopsies from all participants were subjected to RNA sequencing and reclassified by B-cell molecular signature. The study was powered to test the superiority of tocilizumab over rituximab in the B-cell poor population at 16 weeks. The primary endpoint was defined as a 50% improvement in Clinical Disease Activity Index (CDAI50%) from baseline. The trial is registered on the ISRCTN database, ISRCTN97443826, and EudraCT, 2012-002535-28.
Between Feb 28, 2013, and Jan 17, 2019, 164 patients were classified histologically and were randomly assigned to the rituximab group (83 51%) or the tocilizumab group (81 49%). In patients histologically classified as B-cell poor, there was no statistically significant difference in CDAI50% between the rituximab group (17 45% of 38 patients) and the tocilizumab group (23 56% of 41 patients; difference 11% 95% CI −11 to 33, p=0·31). However, in the synovial biopsies classified as B-cell poor with RNA sequencing the tocilizumab group had a significantly higher response rate compared with the rituximab group for CDAI50% (rituximab group 12 36% of 33 patients vs tocilizumab group 20 63% of 32 patients; difference 26% 2 to 50, p=0·035). Occurrence of adverse events (rituximab group 76 70% of 108 patients vs tocilizumab group 94 80% of 117 patients; difference 10% –1 to 21) and serious adverse events (rituximab group 8 7% of 108 vs tocilizumab group 12 10% of 117; difference 3% –5 to 10) were not significantly different between treatment groups.
The results suggest that RNA sequencing-based stratification of rheumatoid arthritis synovial tissue showed stronger associations with clinical responses compared with histopathological classification. Additionally, for patients with low or absent B-cell lineage expression signature in synovial tissue tocilizumab is more effective than rituximab. Replication of the results and validation of the RNA sequencing-based classification in independent cohorts is required before making treatment recommendations for clinical practice.
Efficacy and Mechanism Evaluation programme from the UK National Institute for Health Research.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This review takes stock of the global health governance (GHG) literature. We address the transition from international health governance (IHG) to global health governance, identify major actors, and ...explain some challenges and successes in GHG. We analyze the framing of health as national security, human security, human rights, and global public good, and the implications of these various frames. We also establish and examine from the literature GHG's major themes and issues, which include: 1) persistent GHG problems; 2) different approaches to tackling health challenges (vertical, horizontal, and diagonal); 3) health's multisectoral connections; 4) neoliberalism and the global economy; 5) the framing of health (e.g. as a security issue, as a foreign policy issue, as a human rights issue, and as a global public good); 6) global health inequalities; 7) local and country ownership and capacity; 8) international law in GHG; and 9) research gaps in GHG. We find that decades-old challenges in GHG persist and GHG needs a new way forward. A framework called shared health governance offers promise.
Objective Synovial fluid (SF)–derived T cells are frequently studied as a proxy for investigating the synovial tissue (ST) T cell infiltrate in inflammatory arthritis. However, because ST is the ...primary site of inflammatory activity, there is debate as to whether SF provides a true reflection of the ST T cell population. Methods In this study, we used single‐cell RNA sequencing paired with single‐cell T cell receptor (TCR) sequencing to directly compare memory T cells from paired samples of SF and ST from six patients with inflammatory arthritis to investigate their similarity in terms of TCR repertoire and T cell subset composition. Results The TCR repertoires of SF and ST T cells were strikingly similar, particularly for CD8+ T cells. A median of 49% of the total CD8+ TCR repertoire in SF was shared with ST, compared with 20% shared with blood. Similarly, 47% of the ST CD8+ TCR repertoire was shared with SF compared to 25% with blood. Furthermore, once the effect of collagenase digestion on gene expression by ST T cells had been accounted for, the frequencies of specific CD8+ and CD4+ T cell subsets were, in general, similar in SF and ST and were distinct from blood. Conclusion Our results suggest that T cells migrate and equilibrate between the SF and ST and maintain similar phenotypes in both sites. We conclude that SF is an appropriate proxy for investigating the T cell infiltrate in inflamed synovium, particularly in terms of investigating the TCR repertoire. image
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
Background/Aims
In England, patients with rheumatoid arthritis (RA) with Moderate Disease Activity (MDAS), assessed by the DAS28 measure, had been unable to access effective therapies. We ...and others have reported that this group has persistent active disease, progressive joint damage, poor function and quality of life for years. In 2021 NICE published Technology Appraisals, 676, 715 and 744, which provided these patients with access to effective advanced therapies. We audited our response to these new standards from their approval in 2021.
Methods
Virtual Biologics Clinic (VBC) electronic records were analysed for details of patients with RA with DAS28 scores ≥3.2 to ≤ 5.1 who were approved for advanced therapies and their response to therapy. Response is reported as those who achieved DAS28 remission or low disease activity (LDAS), the usual goals of therapy for treat to target in patients with RA. Adverse events and reasons for adopting oral therapies were recorded.
Results
Local approval was granted for filgotinib in May 2021, adalimumab, etanercept and infliximab in October 2021, and upadacitinib in February 2022. From May 2021 until 30 August 2022, 49 patients with MDAS status RA have been approved by our VBC process. Of these, 3 declined advanced therapy after approval, 25 started adalimumab, 14 filgotinib, 4 etanercept, 1 certolizumab pegol (planned pregnancy) and 2 with a mixed RA/CTD diagnosis, rituximab. The mean DAS28 score was 4.32, range 3.22-5.1, with 20 having a DAS28 score >4.5. 29 patients had failed two DMARDS, 18 triple therapy and 2 patients failed 4 DMARDs. Most patients starting filgotinib strongly preferred oral therapy and one was a frequent traveller.
Of the 18 patients receiving TNFi therapy who had at least 3 months therapy for initial disease response assessment, 8 achieved DAS 28 remission, 5 LDAS, 3 unchanged and 2 primary failure. In the 11 patients receiving filgotinib for at least three months, 7 achieved DAS28 remission, 2 LDAS, 1 primary failure and I was lost to follow-up. No patients stopped for adverse events to date.
Conclusion
Our preliminary data describing the use of advanced therapies in this previously under-treated group of patients with RA, show that good responses occur in many. A high percentage achieve remission, the primary goal of treat-to target guided therapy in RA.
Disclosure
F. Humby: Honoraria; Galapagos, Roche. Grants/research support; Pfizer. S. Subesinghe: None. A. Cope: Honoraria; Abbvie. B. Menon: None. R. Byng-Maddock: None. N. Ladha Hassan: None. L. Blackler: Honoraria; Abbvie, Novartis, UCB. Z. Mckee: None. K. Topping: None. L. Marsh: None. T. Garrood: Honoraria; UCB. Grants/research support; Galapagos, Pfizer. N. Ng: None. B.W. Kirkham: Honoraria; Abbvie, Galapagos, Janssen, Lilly, Novartis, PfizerUCB. Grants/research support; Lilly, Novartis.
To determine whether SLE patients with inflammatory joint symptoms and US synovitis/tenosyovitis achieve better clinical responses to glucocorticoids compared with patients with normal scans. ...Secondary objectives included identification of clinical features predicting US synovitis/tenosynovitis.
In a longitudinal multicentre study, SLE patients with physician-diagnosed inflammatory joint pain received intramuscular methylprednisolone 120 mg once. Clinical assessments, patient-reported outcomes and bilateral hand/wrist USs were collected at 0, 2 and 6 weeks. The primary outcome (determined via internal pilot) was the early morning stiffness visual analogue scale (EMS-VAS) at 2 weeks, adjusted for baseline, comparing patients with positive (greyscale ≥2 and/or power Doppler ≥1) and negative US. Post hoc analyses excluded FM.
Of 133 patients, 78 had a positive US. Only 53 (68%) of these had one or more swollen joint. Of 66 patients with one or more swollen joint, 20% had a negative US. A positive US was associated with joint swelling, symmetrical small joint distribution and serology. The primary endpoint was not met: in the full analysis set (N = 133) there was no difference in baseline-adjusted EMS-VAS at week 2 -7.7 mm (95% CI -19.0, 3.5); P = 0.178. After excluding 32 patients with FM, response was significantly better in patients with a positive US at baseline baseline-adjusted EMS-VAS at 2 weeks -12.1 mm (95% CI -22.2, -0.1); P = 0.049. This difference was greater when adjusted for treatment -12.8 mm (95% CI -22, -3); P = 0.007. BILAG and SLEDAI responses were higher in US-positive patients.
In SLE patients without FM, those with a positive US had a better clinical response to therapy. Imaging-detected synovitis/tenosynovitis may be considered to decide on therapy and enrich clinical trials.
Objective
To define the relationship of synovial B cells to clinical phenotypes at different stages of disease evolution and drug exposure in rheumatoid arthritis (RA).
Methods
Synovial biopsy ...specimens and demographic and clinical data were collected from 2 RA cohorts (n = 329), one of patients with untreated early RA (n = 165) and one of patients with established RA with an inadequate response to tumor necrosis factor inhibitors (TNFi‐IR; n = 164). Synovial tissue was subjected to hematoxylin and eosin and immunohistochemical staining and semiquantitative assessment for the degree of synovitis (on a scale of 0–9) and of CD20+ B cell infiltrate (on a scale of 0–4). B cell scores were validated by digital image analysis and B cell lineage–specific transcript analysis (RNA‐Seq) in the early RA (n = 91) and TNFi‐IR (n = 127) cohorts. Semiquantitative CD20 scores were used to classify patients as B cell rich (≥2) or B cell poor (<2).
Results
Semiquantitative B cell scores correlated with digital image analysis quantitative measurements and B cell lineage–specific transcripts. B cell–rich synovitis was present in 35% of patients in the early RA cohort and 47.7% of patients in the TNFi‐IR cohort (P = 0.025). B cell–rich patients showed higher levels of disease activity and seropositivity for rheumatoid factor and anti–citrullinated protein antibody in early RA but not in established RA, while significantly higher histologic synovitis scores in B cell–rich patients were demonstrated in both cohorts.
Conclusion
We describe a robust semiquantitative histologic B cell score that closely replicates the quantification of B cells by digital or molecular analyses. Our findings indicate an ongoing B cell–rich synovitis, which does not seem to be captured by standard clinimetric assessment, in a larger proportion of patients with established RA than early RA.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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