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3. POS0138 RHEUMATOID SYNOVIAL FIBROBLASTS DISPLAY IMPRINTED MEMORY OF THEIR SYNOVIAL ENDOTYPE WHICH CAN BE PLASTICALLY MODULATED BY B-CELLS CROSSTALK

Author

Prediletto, E., primary, Cubuk, C., additional, Pontarini, E., additional, Rivellese, F., additional, Nerviani, A., additional, Lucchesi, D., additional, Caliste, M., additional, Corsiero, E., additional, Hands, R., additional, Lewis, M., additional, Pitzalis, C., additional, and Bombardieri, M., additional

Published
2022
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6. B Cell Synovitis and Clinical Phenotypes in Rheumatoid Arthritis: Relationship to Disease Stages and Drug Exposure.

Author

UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de rhumatologie, Rivellese, F, Humby, F, Bugatti, S, Fossati-Jimack, L, Rizvi, H, Lucchesi, D, Lliso-Ribera, G, Nerviani, A, Hands, R E, Giorli, G, Frias, B, Thorborn, G, Jaworska, E, John, C, Goldmann, K, Lewis, M J, Manzo, A, Bombardieri, M, Pitzalis, C, PEAC-R4RA Investigators, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de rhumatologie, Rivellese, F, Humby, F, Bugatti, S, Fossati-Jimack, L, Rizvi, H, Lucchesi, D, Lliso-Ribera, G, Nerviani, A, Hands, R E, Giorli, G, Frias, B, Thorborn, G, Jaworska, E, John, C, Goldmann, K, Lewis, M J, Manzo, A, Bombardieri, M, Pitzalis, C, and PEAC-R4RA Investigators

Abstract

To define the relationship of synovial B cells to clinical phenotypes at different stages of disease evolution and drug exposure in rheumatoid arthritis (RA). 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). 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. 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.

Published
2020

7. OP0217 INVOLVEMENT OF LARGE JOINTS AT DISEASE PRESENTATION IS ASSOCIATED WITH DIVERSE HISTOPATHOLOGICAL FEATURES AND CLINICAL OUTCOMES IN EARLY RHEUMATOID ARTHRITIS

Author

Rivellese, F., primary, Humby, F., additional, Lliso Ribera, G., additional, Nerviani, A., additional, Sciacca, E., additional, Giorli, G., additional, Hands, R., additional, Fossati-Jimack, L., additional, Thorborn, G., additional, Lewis, M., additional, and Pitzalis, C., additional

Published
2020
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16. B Cell Synovitis and Clinical Phenotypes in Rheumatoid Arthritis: Relationship to Disease Stages and Drug Exposure.

Author

Rivellese, F., Humby, F., Bugatti, S., Fossati‐Jimack, L., Rizvi, H., Lucchesi, D., Lliso‐Ribera, G., Nerviani, A., Hands, R. E., Giorli, G., Frias, B., Thorborn, G., Jaworska, E., John, C., Goldmann, K., Lewis, M. J., Manzo, A., Bombardieri, M., Pitzalis, C., and McInnes, Iain B.

Subjects
B cells, IMMUNOHISTOCHEMISTRY, LONGITUDINAL method, RHEUMATOID arthritis, RNA, TUMOR necrosis factors, PHENOTYPES, SYNOVITIS, SEVERITY of illness index, DESCRIPTIVE statistics
Abstract

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. [ABSTRACT FROM AUTHOR]

Published
2020
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18. Magnetic Molecules

Author

Hands, R. A.

Abstract

Describes the use of disc or ring magnets magetized axially and iron discs, in conjunction with an overhead projector, as a model of nuclear structure and of complete molecules. (GS)

Published
1975

19. OP0040 Synovial cell infiltration in acpa-ve patients displays similar signatures to other seronegative inflammatory arthritis. results from the pathobiology of early arthritis cohort (PEAC)

Author

Lliso-Ribera, G., primary, Humby, F., additional, Nerviani, A., additional, Boutet, M.A., additional, Kelly, S., additional, Bombardieri, M., additional, Lewis, M., additional, Hands, R., additional, Rocher, V., additional, Bene, F., additional, Buckley, C., additional, Taylor, P.C., additional, McInnes, I.B., additional, and Pitzalis, C., additional

Published
2018
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23. FRI0088 Synovial pathobiology correlates with diagnostic subgroups in early inflammatory arthritis: results from the pathobiology of early arthritis cohort (PEAC)

Author

Lliso-Ribera, G, primary, Humby, F, additional, Kelly, S, additional, Bombardieri, M, additional, Lewis, M, additional, Hands, R, additional, Rocher, V, additional, Bene, F, additional, Nerviani, A, additional, Buckely, C, additional, Taylor, P, additional, McInnes, I, additional, and Pitzalis, C, additional

Published
2017
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24. THU0100 In early inflammatory arthritis a lymphoid pathotype signficantly associates with requirement for biologic therapy at 12 months follow up: results from the pathobiology of early arthritis cohort (PEAC)

Author

Lliso-Ribera, G, primary, Humby, F, additional, Kelly, S, additional, Bombardieri, M, additional, Lewis, M, additional, Hands, R, additional, Rocher, V, additional, Bene, F, additional, Nerviani, A, additional, Buckely, C, additional, Taylor, P, additional, McInnes, I, additional, and Pitzalis, C, additional

Published
2017
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26. OP0240 Synovial Lymphocytic Aggregates Associate with Highly Active RA and Predict Erosive Disease Progression at 12 Months: Results from The Pathobiology of Early Arthritis Cohort

Author

Humby, F., primary, Dicicco, M., additional, Kelly, S., additional, Bombardieri, M., additional, Hands, R., additional, Rocher, V., additional, Zou, L., additional, Myles, L., additional, Blighe, K., additional, Ng, N., additional, Ramamoorthi, N., additional, Hackney, J., additional, Zuckerman, N., additional, Townsend, M., additional, Landewe, R., additional, Van der Helm van Mihl, A., additional, van der Heijde, D., additional, Buckely, C., additional, Taylor, P., additional, McInnes, I., additional, and Pitzalis, C., additional

Published
2016
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28. Ultrasound-guided synovial biopsy: A safe, well-tolerated and reliable technique for obtaining high-quality synovial tissue from both large and small joints in early arthritis patients

Author

Kelly, S., Humby, F., Filer, A., Ng, N., Di Cicco, M., Hands, R. E., Rocher, V., Bombardieri, M., D'Agostino, Maria Antonietta, Mcinnes, I. B., Buckley, C. D., Taylor, P. C., Pitzalis, C., D'Agostino M. A. (ORCID:0000-0002-5347-0060), Kelly, S., Humby, F., Filer, A., Ng, N., Di Cicco, M., Hands, R. E., Rocher, V., Bombardieri, M., D'Agostino, Maria Antonietta, Mcinnes, I. B., Buckley, C. D., Taylor, P. C., Pitzalis, C., and D'Agostino M. A. (ORCID:0000-0002-5347-0060)

Abstract

Objective: To determine the tolerability, safety and yield of synovial tissue in an early arthritis cohort using a minimally invasive, ultrasound (US)-guided, synovial biopsy technique in small, medium and large joints. Methods: 93 sequential biopsy procedures were assessed from a total of 57 patients (baseline and 36 repeat biopsies at 6 months) recruited as part of the 'Pathobiology of Early Arthritis Cohort' study. Patients completed a tolerability questionnaire prior to and following the synovial biopsy procedure. The synovial biopsy was performed under US guidance with US images of the joint recorded prior to each procedure. Synovial tissue was harvested for immunohistochemistry and RNA extraction. Results: Five different joint sites were biopsied (knee, elbow, wrist, metacarpal phalangeal and proximal interphalangeal). No significant complications were reported following the procedure. No difference in pain, swelling and stiffness of the biopsied joint from before and after the procedure was demonstrated. A median of 14 biopsy samples was retrieved from each procedure with 93% of biopsy procedures yielding good quality tissue. RNA yield was good in all joints and in repeat biopsies. Multivariant analysis demonstrated a significantly greater yield of RNA and graded tissue in relation to a high prebiopsy, grey-scale synovitis score (0-3, semiquantitative). Conclusions: A minimally invasive approach to synovial tissue harvesting, using US guidance, is both safe and well-tolerated by patients. Tissue quality/RNA yield is preserved in subsequent biopsies following therapeutic intervention. A high US grey-scale synovitis score is a predictor of good quality/quantity of tissue and RNA.

Published
2015

29. OP0208 Synovial Immunopathology Defines Clinical Responsiveness to Dmard Therapy in Early Psoriatic Arthritis: A Pre- and Post-Treatment Mechanistic Study Using a Minimally Invasive Ultrasound-Guided Synovial Biopsy Procedure

Author

Tan, W.S., primary, Bellan, M., additional, Nerviani, A., additional, Di Cicco, M., additional, Mahto, A., additional, Lazarou, I., additional, Hands, R., additional, Humby, F., additional, Kelly, S., additional, and Pitzalis, C., additional

Published
2015
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35. Ultrasound-guided synovial biopsy: a safe, well-tolerated and reliable technique for obtaining high-quality synovial tissue from both large and small joints in early arthritis patients

Author

Kelly, S, primary, Humby, F, additional, Filer, A, additional, Ng, N, additional, Di Cicco, M, additional, Hands, R E, additional, Rocher, V, additional, Bombardieri, M, additional, D'Agostino, M A, additional, McInnes, I B, additional, Buckley, C D, additional, Taylor, P C, additional, and Pitzalis, C, additional

Published
2013
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44. Differential Expression Patterns of the Insulin-Like Growth Factor 2 Gene in Human Colorectal Cancer

Author

Li, S.-R., Ng, C.F.J., Banerjea, A., Ahmed, S., Hands, R., Powar, M., Ogunkolade, W., Dorudi, S., and Bustin, S.A.

Abstract

AbstractTumour development and metastasis are associated with altered gene expression profiles. The aim of this study was to identify the transcriptional differences in normal, tumour and metastatic tissue. We used oligonucleotide arrays to identify differential expression patterns of insulin-like growth factor 2 (IGF 2) between 139 primary colorectal tumour specimens and 42 tumour-adjacent mucosa specimens from colorectal cancer (CRC) patients. The expression levels of the IGF 2 gene were significantly increased in primary tumours compared with adjacent mucosae. This was concordant with our real-time RT-PCR quantification of 48 matched tumour mucosa samples. IGF 2 expression levels were also measured by RT-PCR quantitative analysis in 18 liver metastases and 10 normal tissues from patients without cancer. The mRNA levels were significantly under-expressed in liver metastases compared with either colorectal tumours or adjacent normal mucosae. The non- malignant normal tissue expressed significantly lower IGF 2 levels than adjacent normal tissue, and this was not due to a field effect originating from the tumour. In addition, our microarray data demonstrated that IGF 2 expression was down-regulated in sporadic microsatellite instability (MSI-H) CRC and parallels under-expression of hMLH1 and IGF 2 receptor genes in these patients. We conclude that IGF 2 plays an important role in CRC development. Also, individuals with loss of genomic imprinting (LOI) causing over-expression of IGF 2 may be at greater risk of developing CRC. However, this LOI may be reversed in MSI-H patients.Copyright © 2004 S. Karger AG, Basel

Published
2004

46. Calculation of Wavelengths from Reflecting Echelon Patterns

Author

Hands, R. A., Heslop, W. A., and Littlefield, T. A.

Abstract

Wavelengths are calculated from measurements of reflecting echelon patterns by a simplified procedure which can be carried out conveniently, using a digital computer. By measuring to the position of the centre of the envelope, rather than to an arbitrary mirror image as hitherto, it is shown that envelope correction is automatically applied and a very simple correction for non-linearity of dispersion may be made where necessary.

Published
1960
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47. Colorectal cancers with microsatellite instability display mRNA expression signatures characteristic of increased immunogenicity

Author

Bustin Stephen A, Feakins Roger, Shaw Peter M, Han Xia, Huang Fei, Hands Rebecca E, Ahmed Shafi, Banerjea Ayan, and Dorudi Sina

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Colorectal cancers displaying high-degree microsatellite instability (MSI-H) have an improved prognosis compared to microsatellite stable (MSS) cancers. The observation of pronounced lymphocytic infiltrates suggests that MSI-H cancers are inherently more immunogenic. We aimed to compare the gene expression profiles of MSI-H and MSS cancers to provide evidence for an activated immune response in the former. Results We analysed tissue from 133 colorectal cancer patients with full consent and Local Ethics Committee approval. Genomic DNA was analysed for microsatellite instability in BAT-26. High-quality RNA was used for microarray analysis on the Affymetrix® HG-U133A chip. Data was analysed on GeneSpring software version 6.0. Confirmatory real-time RT-PCR was performed on 28 MSI-H and 26 MSS cancers. A comparison of 29 MSI-H and 104 MSS cancers identified 2070 genes that were differentially expressed between the two groups [P < 0.005]. Significantly, many key immunomodulatory genes were up-regulated in MSI-H cancers. These included antigen chaperone molecules (HSP-70, HSP-110, Calreticulin, gp96), pro-inflammatory cytokines (Interleukin (IL)-18, IL-15, IL-8, IL-24, IL-7) and cytotoxic mediators (Granulysin, Granzyme A). Quantitative RT-PCR confirmed up-regulation of HSP-70 [P = 0.016], HSP-110 [P = 0.002], IL-18 [P = 0.004], IL-8 [0.002] and Granulysin [P < 0.0001]. Conclusions The upregulation of a large number of genes implicated in immune response supports the theory that MSI-H cancers are immunogenic. The novel observation of Heat Shock Protein up-regulation in MSI-H cancer is highly significant in light of the recognised roles of these proteins in innate and antigen-specific immunogenicity. Increased mRNA levels of pro-inflammatory cytokines and cytotoxic mediators also indicate an activated anti-tumour immune response.

Published
2004
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50. A Pauci-Immune Synovial Pathotype Predicts Inadequate Response to TNFα-Blockade in Rheumatoid Arthritis Patients

Author

Frances Humby, Georgina Thorborn, Daniele Mauro, Marie-Astrid Boutet, Arti Mahto, Maria Di Cicco, Felice Rivellese, Myles Lewis, Mattia Bellan, Rebecca Hands, Costantino Pitzalis, Giovanni Giorli, Gloria Lliso-Ribera, Michele Bombardieri, Stephen Kelly, Alessandra Nerviani, Nerviani, A., Di Cicco, M., Mahto, A., Lliso-Ribera, G., Rivellese, F., Thorborn, G., Hands, R., Bellan, M., Mauro, D., Boutet, M. -A., Giorli, G., Lewis, M., Kelly, S., Bombardieri, M., Humby, F., and Pitzalis, C.

Subjects
Male, 0301 basic medicine, rheumatoid arthritis, T-Lymphocytes, Gastroenterology, Arthritis, Rheumatoid, 0302 clinical medicine, Immunology and Allergy, Medicine, Certolizumab pegol, Original Research, CD20, synovial tissue, biology, CD68, Synovial Membrane, Middle Aged, Prognosis, Immunohistochemistry, Biological Therapy, Treatment Outcome, medicine.anatomical_structure, certolizumab-pegol, Antirheumatic Agents, Rheumatoid arthritis, Female, medicine.symptom, medicine.drug, Adult, lcsh:Immunologic diseases. Allergy, medicine.medical_specialty, Plasma Cells, Immunology, 03 medical and health sciences, Internal medicine, Humans, Endoscopic Ultrasound-Guided Fine Needle Aspiration, Tumor Necrosis Factor-alpha, business.industry, Macrophages, pathotype, rheumatoid arthriti, Metacarpophalangeal joint, anti-TNF, medicine.disease, 030104 developmental biology, Pauci-immune, Certolizumab Pegol, biology.protein, Histopathology, business, lcsh:RC581-607, Follow-Up Studies, 030215 immunology
Abstract

Objectives: To assess whether the histopathological features of the synovium before starting treatment with the TNFi certolizumab-pegol could predict clinical outcome and examine the modulation of histopathology by treatment. Methods: Thirty-seven RA patients fulfilling UK NICE guidelines for biologic therapy were enrolled at Barts Health NHS trust and underwent synovial sampling of an actively inflamed joint using ultrasound-guided needle biopsy before commencing certolizumab-pegol and after 12-weeks. At 12-weeks, patients were categorized as responders if they had a DAS28 fall >1.2. A minimum of 6 samples was collected for histological analysis. Based on H&E and immunohistochemistry (IHC) staining for CD3 (T cells), CD20 (B cells), CD138 (plasma cells), and CD68 (macrophages) patients were categorized into three distinct synovial pathotypes (lympho-myeloid, diffuse-myeloid, and pauci-immune). Results: At baseline, as per inclusion criteria, DAS28 mean was 6.4 ± 0.9. 94.6% of the synovial tissue was retrieved from the wrist or a metacarpophalangeal joint. Histological pathotypes were distributed as follows: 58% lympho-myeloid, 19.4% diffuse-myeloid, and 22.6% pauci-immune. Patients with a pauci-immune pathotype had lower levels of CRP but higher VAS fatigue compared to lympho- and diffuse-myeloid. Based on DAS28 fall >1.2, 67.6% of patients were deemed as responders and 32.4% as non-responders. However, by categorizing patients according to the baseline synovial pathotype, we demonstrated that a significantly higher number of patients with a lympho-myeloid and diffuse-myeloid pathotype in comparison with pauci-immune pathotype [83.3% (15/18), 83.3 % (5/6) vs. 28.6% (2/7), p = 0.022) achieved clinical response to certolizumab-pegol. Furthermore, we observed a significantly higher level of post-treatment tender joint count and VAS scores for pain, fatigue and global health in pauci-immune in comparison with lympho- and diffuse-myeloid patients but no differences in the number of swollen joints, ESR and CRP. Finally, we confirmed a significant fall in the number of CD68+ sublining macrophages post-treatment in responders and a correlation between the reduction in the CD20+ B-cells score and the improvement in the DAS28 at 12-weeks. Conclusions: The analysis of the synovial histopathology may be a helpful tool to identify among clinically indistinguishable patients those with lower probability of response to TNFα-blockade.

Published
2020
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