Publications by authors named "Paul Peter Tak"

60 Publications

A randomised, placebo-controlled study of RIPK1 inhibitor GSK2982772 in patients with active ulcerative colitis.

BMJ Open Gastroenterol 2021 08;8(1)

Pharmaceuticals Research and Development, GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire, UK.

Objective: Tumour necrosis factor signalling via the receptor-interacting protein kinase 1 (RIPK1) pathway regulates colonic inflammation suggesting that RIPK1 inhibition may be a potential therapeutic target in ulcerative colitis (UC). This phase IIa, randomised, double-blind experimental medicine study investigated the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of the RIPK1 inhibitor GSK2982772 in patients with active UC.

Design: In part A, prior to a protocol amendment, one patient was randomised to receive GSK2982772 60 mg twice daily for 42 days. After the amendment, patients were randomised 2:1 to receive GSK2982772 60 mg or placebo three times daily for 42 days. In part B, all patients switched to open-label GSK2982772 60 mg three times daily for 42 days. Safety, PK, PD biomarkers, histological disease activity, clinical efficacy and quality of life were assessed at days 43 and 85.

Results: Thirty-six patients were randomised (n=12, placebo/open-label GSK2982772; n=24, GSK2982772/open-label GSK2982772). Most adverse events were mild, with headache reported the most frequently across groups (placebo/open-label GSK2982772, n=2 (17%); GSK2982772/open-label GSK2982772, n=8 (33%)). GSK2982772 was well distributed into colonic tissue, with generally higher concentrations in colonic biopsy samples versus plasma. No apparent differences between treatment groups were observed for PD, histological disease activity, clinical disease activity or quality-of-life measures. At screening, all patients had Mayo endoscopic scores of 2 or 3. At day 43, no patients in the placebo/open-label GSK2982772 group achieved Mayo endoscopic scores of 0 or 1 vs 3/24 (13%) for GSK2982772/open-label GSK2982772. At day 85, 1/9 (11%) achieved scores of 0 or one for placebo/open-label GSK2982772 vs 3/22 (14%) for GSK2982772/open-label GSK2982772.

Conclusion: GSK2982772 was generally well tolerated, with no treatment-related safety concerns identified. However, no significant differences in efficacy were observed between treatment groups, suggesting that GSK2982772 as monotherapy is not a promising treatment for patients with active UC.

Trial Registration Number: NCT02903966.
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http://dx.doi.org/10.1136/bmjgast-2021-000680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365785PMC
August 2021

A randomized, placebo-controlled experimental medicine study of RIPK1 inhibitor GSK2982772 in patients with moderate to severe rheumatoid arthritis.

Arthritis Res Ther 2021 03 16;23(1):85. Epub 2021 Mar 16.

GlaxoSmithKline Medicine Research Center, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.

Background: Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of inflammation through cell death and proinflammatory cytokine production. This multicenter, randomized, double-blind (sponsor-unblinded), placebo-controlled, experimental medicine study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in moderate to severe rheumatoid arthritis (RA).

Methods: Patients with moderate to severe RA who had received ≥12 weeks' stable-dose conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy were randomized (2:1) to GSK2982772 60 mg or placebo orally 2 or 3 times daily for 84 days. Safety, PK, disease activity, joint damage, and pharmacodynamic (PD) biomarkers were assessed at days 43 and 85.

Results: A total of 52 patients were randomized (placebo, 18; GSK2982772, 34). Adverse events (AEs) were reported in 13 (72%) in patients in the placebo group (n = 3 b.i.d; n = 10 t.i.d.) and 20 (61%) in the GSK2982772 group (n = 3 b.i.d; n = 17 t.i.d.). All treatment-related AEs were mild/moderate, except one severe case of alopecia areata at day 49 and retinal vein thrombosis at day 66 (which led to withdrawal from the study) in patients receiving GSK2982772 t.i.d. Disease Activity Score in 28 Joints-C-reactive protein (DAS28-CRP) scores, ACR20/50/70 response, and rates of low disease activity and remission were similar between placebo and GSK2982772 arms.

Conclusions: These results suggest that inhibition of RIPK1 activity at the GSK2982772 exposure levels evaluated do not translate into meaningful clinical improvement of RA.

Trial Registration: ClinicalTrials.gov Identifier: NCT02858492 . Registered 8 August 2016.
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http://dx.doi.org/10.1186/s13075-021-02468-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962407PMC
March 2021

cDC1 are required for the initiation of collagen-induced arthritis.

J Transl Autoimmun 2020 16;3:100066. Epub 2020 Sep 16.

Department of Clinical Immunology and Rheumatology.

Rheumatoid arthritis (RA) is chronic autoimmune disease which etiology remains unknown. Several cell types have been described to potentiate/aggravate the arthritic process however the initiating event in synovial inflammation is still elusive. Dendritic cells (DCs) are essential for the initiation of primary immune responses and thus we hypothesized that these cells might be crucial for RA induction. DCs are a heterogeneous population of cells comprising different subsets with distinct phenotype and function. Here we investigated which DC subset(s) is/are crucial for the initiation of the arthritic process. We have previously demonstrated that Flt3-/- mice, with reduced DCs, were protected from collagen induced arthritis (CIA). Here we have shown that GM-CSF derived DCs in Flt3L-/- mice are functional but not sufficient to induce arthritis. Batf3 mice lacking both CD103 and CD8α cDC1 were resistant to collagen induced arthritis (CIA), demonstrating that this DC subset is crucial for arthritis development. CEP-701 (a Flt3L inhibitor) treatment prevented CIA induction, and reduced dramatically the numbers CD103 cDC1s present in the lymph nodes and synovium. Hence this study identified cDC1 as the main subset orchestrating the initiation of cell-mediated immunity in arthritis.
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http://dx.doi.org/10.1016/j.jtauto.2020.100066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522802PMC
September 2020

Response to Inhibition of Receptor-Interacting Protein Kinase 1 (RIPK1) in Active Plaque Psoriasis: A Randomized Placebo-Controlled Study.

Clin Pharmacol Ther 2020 10 7;108(4):808-816. Epub 2020 Jul 7.

GlaxoSmithKline, Stevenage, UK.

Receptor-interacting protein kinase 1 (RIPK1), a regulator of inflammation and cell death, is a potential therapeutic target in immune-mediated inflammatory diseases (IMIDs). The objective of this phase IIa multicenter, randomized, double-blind, placebo-controlled study was to evaluate safety, tolerability pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in plaque-type psoriasis. Psoriasis patients (N = 65) were randomized to 60 mg twice daily (b.i.d.) or three times daily (t.i.d.), or placebo for 84 days. Most adverse events (AEs) were mild with no severe drug-related AEs reported. Plaque Lesion Severity Sum improved with b.i.d. treatment compared with placebo; interpretation of t.i.d. treatment results was complicated by a high placebo response. Reductions in epidermal thickness and infiltration by CD3+ T cells in the epidermis and dermis were observed compared with placebo. Results support the rationale for additional studies on RIPK1 inhibition in IMIDs.
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http://dx.doi.org/10.1002/cpt.1852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540322PMC
October 2020

Incidence and risk factors for adalimumab and infliximab anti-drug antibodies in rheumatoid arthritis: A European retrospective multicohort analysis.

Semin Arthritis Rheum 2019 06 12;48(6):967-975. Epub 2018 Oct 12.

INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Paris-Sud University, Paris-Saclay University, Le Kremlin-Bicêtre, France; Department of Rheumatology, AP-HP, Paris-Sud University Hospitals, Le Kremlin Bicêtre Hospital, Le Kremlin-Bicêtre, France. Electronic address:

Objectives: To evaluate the incidence of anti-drug antibody (ADA) occurrences and ADA-related risk factors under adalimumab and infliximab treatment in rheumatoid arthritis (RA) patients.

Methods: The study combined retrospective cohorts from the ABIRISK project totaling 366 RA patients treated with adalimumab (n = 240) or infliximab (n = 126), 92.4% of them anti-TNF naive (n = 328/355) and 96.6% of them co-treated with methotrexate (n = 341/353) with up to 18 months follow-up. ADA positivity was measured by enzyme-linked immunosorbent assay. The cumulative incidence of ADA was estimated, and potential bio-clinical factors were investigated using a Cox regression model on interval-censored data.

Results: ADAs were detected within 18 months in 19.2% (n = 46) of the adalimumab-treated patients and 29.4% (n = 37) of the infliximab-treated patients. The cumulative incidence of ADA increased over time. In the adalimumab and infliximab groups, respectively, the incidence was 15.4% (5.2-20.2) and 0% (0-5.9) at 3 months, 17.6% (11.4-26.4) and 0% (0-25.9) at 6 months, 17.7% (12.6-37.5) and 34.1% (11.4-46.3) at 12 months, 50.0% (25.9-87.5) and 37.5% (25.9-77.4) at 15 months and 50.0% (25.9-87.5) and 66.7% (37.7-100) at 18 months. Factors associated with a higher risk of ADA development were: longer disease duration (1-3 vs. < 1 year; adalimumab: HR 3.0, 95% CI 1.0-8.7; infliximab: HR 2.7, 95% CI 1.1-6.8), moderate disease activity (DAS28 3.2-5.1 vs. < 3.2; adalimumab: HR 6.6, 95% CI 1.3-33.7) and lifetime smoking (infliximab: HR 2.7, 95% CI 1.2-6.3).

Conclusions: The current study focusing on patients co-treated with methotrexate for more than 95% of them found a late occurrence of ADAs not previously observed, whereby the risk continued to increase over 18 months. Disease duration, DAS28 and lifetime smoking are clinical predictors of ADA development.
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http://dx.doi.org/10.1016/j.semarthrit.2018.10.006DOI Listing
June 2019

Fibroblasts and Osteoblasts in Inflammation and Bone Damage.

Adv Exp Med Biol 2018;1060:37-54

Division of Clinical Immunology & Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.

This review discusses the important role fibroblasts play in the process of inflammation and the evidence that these cells may drive the persistence of inflammation. Fibroblasts are key components of the stroma normally involved in maintenance of extracellular matrix and tissue function; however, the term 'fibroblast' is used to describe a heterogeneous population of cells that vary in phenotype both between and within anatomical sites. Fibroblasts possess Toll-like receptors allowing them to respond to pathogen and damage-related signals by producing proinflammatory mediators such as IL-6, PGE, and GM-CSF and can produce a range of chemokines such as CXCL12, CXCL13, and CXCL8 which attract B and T lymphocytes, monocytes, and neutrophils to sites of inflammation. Interactions between leukocytes and fibroblasts can facilitate increased survival of the leukocytes and modulate phenotypes leading to differential gene expression in the presence of mediators involved in inflammation. Fibroblasts also contribute to collateral tissue damage during inflammation through the production of members of the metalloproteinase family and cathepsins and also through induction of osteoclastogenesis leading to increased bone resorption rates. In persistent diseases, fibroblasts obtain an imprinted, aggressive phenotype leading to the production of higher basal levels of proinflammatory cytokines and the ability to damage tissue in the absence of continual stimuli. This aggressive phenotype offers an attractive new target for therapeutics that could help alleviate the burden of persistent inflammation.
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http://dx.doi.org/10.1007/978-3-319-78127-3_3DOI Listing
February 2019

Induction of sustained remission in early inflammatory arthritis with the combination of infliximab plus methotrexate: the DINORA trial.

Arthritis Res Ther 2018 08 9;20(1):174. Epub 2018 Aug 9.

Department of Medicine III, Division of Rheumatology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Background: In the present study, we explored the effects of immediate induction therapy with the anti-tumour necrosis factor (TNF)α antibody infliximab (IFX) plus methotrexate (MTX) compared with MTX alone and with placebo (PL) in patients with very early inflammatory arthritis.

Methods: In an investigator-initiated, double-blind, randomised, placebo-controlled, multi-centre trial (ISRCTN21272423, http://www.isrctn.com/ISRCTN21272423 ), patients with synovitis of 12 weeks duration in at least two joints underwent 1 year of treatment with IFX in combination with MTX, MTX monotherapy, or PL randomised in a 2:2:1 ratio. The primary endpoint was clinical remission after 1 year (sustained for at least two consecutive visits 8 weeks apart) with remission defined as no swollen joints, 0-2 tender joints, and an acute-phase reactant within the normal range.

Results: Ninety patients participated in the present study. At week 54 (primary endpoint), 32% of the patients in the IFX + MTX group achieved sustained remission compared with 14% on MTX alone and 0% on PL. This difference (p < 0.05 over all three groups) was statistically significant for IFX + MTX vs PL (p < 0.05), but not for IFX + MTX vs MTX (p = 0.10), nor for MTX vs PL (p = 0.31). Remission was maintained during the second year on no therapy in 75% of the IFX + MTX patients compared with 20% of the MTX-only patients.

Conclusions: These results indicate that patients with early arthritis can benefit from induction therapy with anti-TNF plus MTX compared with MTX alone, suggesting that intensive treatment can alter the disease evolution.

Trial Registration: The trial was registered at http://www.isrctn.com/ISRCTN21272423 on 4 October 2007 (date applied)/12 December 2007 (date assigned). The first patient was included on 24 October 2007.
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http://dx.doi.org/10.1186/s13075-018-1667-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085639PMC
August 2018

MiR-146a G/C rs2910164 variation in South African Indian and Caucasian patients with psoriatic arthritis.

BMC Med Genet 2018 03 27;19(1):48. Epub 2018 Mar 27.

School of Laboratory Medicine and Medical Sciences, Discipline of Medical Biochemistry and Chemical Pathology, University of KwaZulu-Natal, George Campbell Building - South Entrance, 3rd Floor, King George V Avenue, Howard College Campus, Durban, 4001, South Africa.

Background: Psoriasis and psoriatic arthritis (PsA) are inflammatory associated autoimmune disorders. MicroRNA (miR)-146a plays a crucial role in regulating inflammation. A single nucleotide polymorphism in the miR-146a gene (rs2910164), aberrantly alters its gene expression and linked with the pathogenesis of several disorders, including psoriasis and PsA. In South Africa, psoriasis and PsA are extremely rare in the indigenous African population and most common in both the Indian and Caucasian population. The aim of this study was to investigate whether the miR-146a rs2910164 contributes towards psoriasis and PsA development in South African Indian and Caucasian patients.

Methods: South African Indian (n = 84) and Caucasian (n = 32) PsA patients (total n = 116) and healthy control subjects (Indian: n = 62 and Caucasian: n = 38; total n = 100) were recruited in the study. DNA was extracted from whole blood taken from all subjects, and genotyped for the miR-146a rs2910164 using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Data for laboratory parameters were obtained from pathology reports. The consulting rheumatologist collected all other clinical data.

Results: Unstratified data (Caucasians + Indians): A significant decrease in C-reactive protein (CRP) levels in PsA patients was observed (CRP monitored at inclusion vs. after 6 months of treatment) (18.95 ± 2.81 mg/L vs. 9.68 ± 1.32 mg/L, p = 0.0011). The miR-146a rs2910164 variant C-allele frequency in PsA patients was significantly higher vs. healthy controls (35.78% vs. 26% respectively, p = 0.0295, OR = 1.59 95% CI 1.05-2.40). Stratified data (Indians): The variant C-allele frequency in Indian PsA patients was significantly higher vs. healthy Indian controls (35.71% vs. 22.58%, p = 0.0200, OR = 1.91 95% CI 1.13-3.22). Stratified data (Caucasians): The variant C-allele frequency distribution between Caucasian PsA patients and healthy Caucasian controls was similar.

Conclusion: The rs2910164 variant C-allele may play a role in the progression of PsA in the South African Indian population. The main limitation in this study was the small sample size in the case-control cohorts, with a low overall statistical power (post-hoc power analysis = 19%).
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http://dx.doi.org/10.1186/s12881-018-0565-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870474PMC
March 2018

Rheumatoid arthritis and psoriatic arthritis synovial fluids stimulate prolactin production by macrophages.

J Leukoc Biol 2017 09 22;102(3):897-904. Epub 2017 Jun 22.

Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Prolactin (PRL) is a neuroendocrine hormone that can promote inflammation. We examined the synovial tissue and fluid levels of PRL in patients with inflammatory arthritis, PRL expression in differentiated Mϕs from patients with arthritis and from healthy donors, and the effects of different stimuli on PRL production by Mϕs. PRL levels were measured in paired synovial fluid (SF) and peripheral blood of patients with rheumatoid arthritis (RA, = 19), psoriatic arthritis (PsA, = 11), and gout ( = 11). Synovial-tissue PRL mRNA expression was measured by quantitative PCR in patients with RA ( = 25), PsA ( = 11), and gout ( = 12) and in Mϕs differentiated in SF of patients with RA, PsA, other subtypes of spondyloarthritis (SpA), and gout. Synovial-tissue PRL mRNA expression correlated significantly with clinical disease parameters in patients with RA and PsA, including erythrocyte sedimentation rate (ESR, = 0.424; = 0.049) and disease activity score evaluated in 28 joints (DAS28, = 0.729; = 0.017). Synovial-tissue PRL expression was similar in RA, PsA, and gout. PRL mRNA expression was detected in monocyte-derived Mϕs from patients with RA and was significantly higher ( ≤ 0.01) in Mϕs differentiated in pooled SF from patients with RA and PsA compared with SpA or gout. PRL production by Mϕ differentiation in the SF from patients with RA was not further regulated by stimulation with CD40L, IgG, LPS, or TNF. PRL is produced locally in the synovium of patients with inflammatory arthritis. The production of PRL by Mϕs was increased by unknown components of RA and PsA SF, where it could contribute to disease progression.
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http://dx.doi.org/10.1189/jlb.2A0317-115RRDOI Listing
September 2017

Computational Model Reveals Limited Correlation between Germinal Center B-Cell Subclone Abundancy and Affinity: Implications for Repertoire Sequencing.

Front Immunol 2017 6;8:221. Epub 2017 Mar 6.

Biosystems Data Analysis, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands; Bioinformatics Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.

Immunoglobulin repertoire sequencing has successfully been applied to identify expanded antigen-activated B-cell clones that play a role in the pathogenesis of immune disorders. One challenge is the selection of the Ag-specific B cells from the measured repertoire for downstream analyses. A general feature of an immune response is the expansion of specific clones resulting in a set of subclones with common ancestry varying in abundance and in the number of acquired somatic mutations. The expanded subclones are expected to have BCR affinities for the Ag higher than the affinities of the naive B cells in the background population. For these reasons, several groups successfully proceeded or suggested selecting highly abundant subclones from the repertoire to obtain the Ag-specific B cells. Given the nature of affinity maturation one would expect that abundant subclones are of high affinity but since repertoire sequencing only provides information about abundancies, this can only be verified with additional experiments, which are very labor intensive. Moreover, this would also require knowledge of the Ag, which is often not available for clinical samples. Consequently, in general we do not know if the selected highly abundant subclone(s) are also the high(est) affinity subclones. Such knowledge would likely improve the selection of relevant subclones for further characterization and Ag screening. Therefore, to gain insight in the relation between subclone abundancy and affinity, we developed a computational model that simulates affinity maturation in a single GC while tracking individual subclones in terms of abundancy and affinity. We show that the model correctly captures the overall GC dynamics, and that the amount of expansion is qualitatively comparable to expansion observed from B cells isolated from human lymph nodes. Analysis of the fraction of high- and low-affinity subclones among the unexpanded and expanded subclones reveals a limited correlation between abundancy and affinity and shows that the low abundant subclones are of highest affinity. Thus, our model suggests that selecting highly abundant subclones from repertoire sequencing experiments would not always lead to the high(est) affinity B cells. Consequently, additional or alternative selection approaches need to be applied.
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http://dx.doi.org/10.3389/fimmu.2017.00221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337809PMC
March 2017

B-cell imaging with zirconium-89 labelled rituximab PET-CT at baseline is associated with therapeutic response 24 weeks after initiation of rituximab treatment in rheumatoid arthritis patients.

Arthritis Res Ther 2016 11 18;18(1):266. Epub 2016 Nov 18.

Amsterdam Rheumatology and immunology Center (ARC), location VU University Medical Center, Amsterdam, The Netherlands.

Background: B cells are key players in the pathogenesis of rheumatoid arthritis (RA). Although successful in 50-60% of patients with RA, anti-B-cell therapy given as rituximab could be more efficient by identifying potential responders prior to treatment. Positron emission tomography (PET) using radiolabeled rituximab for B-cell imaging might provide the means to fulfil this unmet clinical need. The objective of this study was to investigate the association between biodistribution of zirconium-89 (Zr)-rituximab on PET-computed tomography (CT) and clinical response in patients with RA.

Methods: We included 20 patients with RA who were starting rituximab treatment. At the first intravenous (i.v.) therapeutic dose, patients were also injected with Zr-rituximab, followed by PET-CT. European League Against Rheumatism (EULAR) response criteria were applied to determine response at week 24. PET-CT was analyzed visually and quantitatively. Lymph node (LN) biopsies were performed at 0 and 4 weeks to correlate B-cell counts with imaging data.

Results: PET-positive hand joints (range 1-20) were observed in 18/20 patients. Responders had significantly higher Zr-rituximab uptake in PET-positive hand joints than non-responders (median target-to-background (T/B)) ratios (IQR) were 6.2 (4.0-8.8) vs. 3.1 (2.2-3.9), p = 0.02). At T/B ≥4.0, positive and negative predictive values for clinical response were respectively 90% and 75%. Quantitative Zr-rituximab hand joint uptake on PET correlated inversely with CD22 B-cell count in LN tissue at 4 weeks of treatment (r = 0.6, p = 0.05). In addition, the CD22 B-cell count in LN correlated positively with quantitative LN PET data at baseline, supporting the specificity of B-cell imaging on PET.

Conclusions: Non-invasive B-cell imaging by Zr-rituximab PET-CT has promising clinical value to select RA responders to rituximab at baseline. Zr-rituximab PET-CT may also hold promise for monitoring anti-B-cell therapies in other B-cell driven autoimmune diseases, such as systemic lupus erythematosus and Sjögren's disease.
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http://dx.doi.org/10.1186/s13075-016-1166-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116204PMC
November 2016

Hormone, metabolic peptide, and nutrient levels in the earliest phases of rheumatoid arthritis-contribution of free fatty acids to an increased cardiovascular risk during very early disease.

Clin Rheumatol 2017 Feb 2;36(2):269-278. Epub 2016 Nov 2.

Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.

Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with changes in several hormones and metabolic peptides. Crosstalk between these factors and the immune system may be important for homeostasis during inflammation. Here, we studied the levels of hormones, metabolic peptides, and nutrients in individuals at risk for developing RA (at risk). In total, 18 hormones, metabolic peptides, and nutrients were measured in fasting serum samples from 45 autoantibody-positive individuals at risk, 22 RA patients, and 16 healthy subjects. Triglyceride (TG) levels were also measured in an independent validation cohort of 32 individuals at risk, 20 early arthritis patients, and 20 healthy controls. We found an elevated TG level in individuals at risk and significantly higher TG levels in RA patients compared to healthy controls. These results were confirmed in the validation cohort. Similarly, free fatty acid (FFA) levels showed an increase in individuals at risk and were significantly higher in RA patients compared to healthy controls. In RA patients, FFA levels were positively correlated with disease activity. Pancreatic polypeptide (PP) and norepinephrine levels were highly significantly increased in individuals at risk and RA patients compared to healthy controls. TG and FFA levels are increased in RA patients and positively correlated with disease activity parameters. The results presented here suggest a role for FFAs in the pathogenesis of RA. Furthermore, PP and norepinephrine may be a biomarker that could assist in the identification of individuals at risk.
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http://dx.doi.org/10.1007/s10067-016-3456-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290053PMC
February 2017

BET bromodomain inhibition reduces maturation and enhances tolerogenic properties of human and mouse dendritic cells.

Mol Immunol 2016 11 3;79:66-76. Epub 2016 Oct 3.

Tytgat Institute for Gastro-Intestinal and Liver Research, Academic Medical Center, Amsterdam, The Netherlands. Electronic address:

Transcription of inflammatory genes is tightly regulated by acetylation and deacetylation of histone tails. An inhibitor of the acetylated-lysine reader bromodomain and extra-terminal domain (BET) proteins, I-BET151, is known to counteract the induction of expression of inflammatory genes in macrophages. We have investigated the effects of I-BET151 on dendritic cell function, including expression of co-stimulatory molecules and cytokines, and capacity for T cell activation. Treatment of mouse bone marrow derived dendritic cells (BMDC) and human monocyte derived DCs (mdDC) with I-BET151 reduced LPS-induced expression of co-stimulatory molecules, as well as the production of multiple cyokines and chemokines. Most strikingly, secretion of IL-6, IL-12 and IL-10 was significantly reduced to 89.7%, 99.9% and 98.6% respectively of that produced by control cells. I-BET151-treated mdDC showed a reduced ability to stimulate proliferation of autologous Revaxis-specific T cells. Moreover, while I-BET151 treatment of BMDC did not affect their ability to polarise ovalbumin specific CD4 CD62L naive T cells towards Th1, Th2, or Th17 phenotypes, an increase in Foxp3 expressing Tregs secreting higher IL-10 levels was observed. Suppression assays demonstrated that Tregs generated in response to I-BET151-treated BMDC displayed anti-proliferative capacity. Finally, evidence that I-BET151 treatment can ameliorate inflammation in vivo in a T cell dependent colitis model is shown. Overall, these results demonstrate marked effects of BET inhibition on DC maturation, reducing their capacity for pro-inflammatory cytokine secretion and T cell activation and enhancing the potential of DC to induce Foxp3 expressing Treg with suppressive properties.
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http://dx.doi.org/10.1016/j.molimm.2016.09.010DOI Listing
November 2016

The prolactin receptor is expressed in rheumatoid arthritis and psoriatic arthritis synovial tissue and contributes to macrophage activation.

Rheumatology (Oxford) 2016 Dec 10;55(12):2248-2259. Epub 2016 Sep 10.

Division of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands.

Objectives: Prolactin (PRL) is a lactation-inducing hormone with immunomodulatory properties and is found at elevated levels in the serum of patients with RA and other rheumatic diseases. The PRL receptor (PRLR) has been shown to be expressed by macrophages in atherosclerotic plaques. The aim of this study was to examine PRLR expression by synovial macrophages and its role in the regulation of macrophage activation.

Methods: Serum monomeric 23 kDa PRL levels were measured in 119 RA patients using a fluoroimmunometric assay. PRLR expression was assessed in synovial tissue of 91 RA, 15 PsA and 8 OA patients by immunohistochemistry and digital image analysis. Double IF was used to identify PRLR-expressing cells. The effects of PRL on monocyte-derived macrophage gene expression were examined by quantitative real-time PCR and ELISA.

Results: Serum PRL levels were similar in female and male RA patients. Median (interquartile range) PRLR expression was significantly higher (P < 0.05) in RA and PsA synovial tissue compared with OA. PRLR colocalized with synovial CD68 macrophages and von Willebrand factor endothelial cells. In vitro, PRLR was prominently expressed in IFN-γ-and IL-10-polarized macrophages compared with other polarizing conditions. PRL by itself had negligible effects on macrophage gene expression, but cooperated with CD40L and TNF to increase expression of pro-inflammatory genes including IL-6, IL-8 and IL-12β.

Conclusions: Synovial PRLR expression is enhanced in patients with inflammatory arthritis compared with OA, and PRL cooperates with other pro-inflammatory stimuli to activate macrophages. These results identify PRL and PRLR as potential new therapeutic targets in inflammatory arthritis.
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http://dx.doi.org/10.1093/rheumatology/kew316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5144667PMC
December 2016

Psoriatic arthritis: An assessment of clinical, biochemical and radiological features in a single-centre South African cohort.

S Afr Med J 2016 May 5;106(6). Epub 2016 May 5.

Department of Internal Medicine, Prince Mshiyeni Memorial Hospital and School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa; Division of Clinical Immunology and Rheumatology, Academic Medical Centre, University of Amsterdam, Netherlands.

Background: Although psoriatic arthritis (PsA) is a well-documented clinical entity, epidemiological, clinical and radiological studies of South African (SA) patients are scarce.

Objectives: To assess clinical, biochemical and radiological features in a single-centre SA cohort.

Methods: We conducted a prospective assessment of the clinical, biochemical and radiological features of 384 consecutive patients with PsA seen at the rheumatology clinic at Prince Mshiyeni Memorial Hospital, Durban, SA, between January 2007 and December 2013. Patients were assessed at enrolment and 6 months after enrolment. They were classified into five groups as described by Moll and Wright, being entered into the group that best described the clinical manifestations. Clinicopathological characteristics recorded at enrolment were age at the time of examination, racial background, personal and family medical history, age and symptoms at the onset of PsA, pattern of joint involvement, joint pain, and the relationship between joint pain and the onset of PsA.

Results: Of the patients, 59.1% had a polyarticular presentation indistinguishable from rheumatoid arthritis, 19.0% had distal interphalangeal involvement, 9.1% had spondyloarthropathy, 11.9% had oligoarthritis and 0.9% had arthritis mutilans. The epidemiological trends (male/female ratio 1.45:1, mean age at onset of arthritis 50.2 (standard deviation 11.8) years, female preponderance in the polyarticular group and male preponderance in the spondyloarthropathy and oligoarticular groups) were similar to trends published elsewhere. A notable characteristic of our cohort was the complete absence of black South Africans with PsA.

Conclusions: The complete absence of black South Africans with PsA is interesting. We anticipate that our findings will prompt genetic studies to isolate both protective and susceptibility genes for further elucidating PsA.
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http://dx.doi.org/10.7196/SAMJ.2016.v106i6.10347DOI Listing
May 2016

Neo-Epitopes--Fragments of Cartilage and Connective Tissue Degradation in Early Rheumatoid Arthritis and Unclassified Arthritis.

PLoS One 2016 28;11(3):e0149329. Epub 2016 Mar 28.

Nordic Bioscience, Herlev, Denmark.

Objective: Tissue destruction in rheumatoid arthritis (RA) is predominantly mediated by matrix metalloproteinases (MMPs), thereby generating protein fragments. Previous studies have revealed that these fragments include MMP-mediated collagen type I, II, and III degradation, citrullinated and MMP-degraded vimentin and MMP degraded C-reactive protein. We evaluated if biomarkers measuring serum levels of specific sequences of the mentioned fragments would provide further information of diagnostic and/or prognostic processes in early arthritis.

Methods: Ninety-two early arthritis patients (arthritis duration<1 year, DMARD naïve) were enrolled. Patients either fulfilled the ACR/EULAR2010 criteria for RA (n = 60) or had unclassified arthritis (UA) (n = 32). Patients fulfilling the RA criteria after 2 years follow-up were classified into non-erosive (n = 25), or erosive disease (n = 13). Concentrations of the biomarkers: C1M, C2M, C3M, VICM and CRPM were measured in baseline serum.

Results: C1M, C3M and CRPM were able to discriminate between the UA and RA baseline diagnosis in 92 patients with an AUROC of 0.64 (95%CI 0.517 to 0.762), 0.73 (95%CI 0.622 to 0.838) and 0.68 (95%CI 0.570 to 0.795). C2M showed a potential for discrimination between non-erosive and erosive disease in 38 patients with an AUROC of 0.75 (95%CI 0.597 to 0.910). All of the applied biomarkers correlated with one or more of the disease activity parameters: DAS28, ESR, CRP, SJC66, TJC68 and/or HAQ.

Conclusion: This is the first study evaluating the applied biomarkers at this early stage of arthritis. C1M, C3M, CRPM might be the best diagnostic marker, whereas high levels of C2M indicated progression of disease at follow-up in early RA patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149329PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4809616PMC
August 2016

Anti-interleukin 6 receptor therapy for hyper-IgD syndrome.

BMJ Case Rep 2015 Oct 29;2015. Epub 2015 Oct 29.

Department of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.

Hyper-IgD syndrome (HIDS) is a rare, severe hereditary autoinflammatory disease characterised by periodic fevers, elevated serum IgD levels and a wide range of symptoms. Although a few randomised controlled trials have been performed in this disorder, there are no straightforward treatment protocols and none of the potential therapies are registered for this indication. We report a case of a young woman with severe HIDS who failed numerous therapies. Eventually, rational treatment with a monoclonal anti-interleukin 6 receptor antibody was initiated. This therapy resulted in an impressive clinical improvement and reduction in the number of hospital admissions per year. This case report underlines the difficulty of finding a suitable treatment for rare, severe inflammatory diseases. Furthermore, we show that treating patients with targeted therapies may result in clinical benefit for the patient, as well as simultaneously teach us more about the pathophysiology of these rare, relatively understudied diseases.
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http://dx.doi.org/10.1136/bcr-2015-210513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636692PMC
October 2015

Expression of Prostaglandin E2 Enzymes in the Synovium of Arthralgia Patients at Risk of Developing Rheumatoid Arthritis and in Early Arthritis Patients.

PLoS One 2015 30;10(7):e0133669. Epub 2015 Jul 30.

Rheumatology research Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden.

Objective: Arthralgia may precede the development of synovial inflammation in autoantibody-positive individuals at risk of developing rheumatoid arthritis (RA). A major pathway involved in pain is the prostaglandin (PG) E2 pathway. We investigated this pathway in the synovium of individuals with RA-specific autoantibodies and in early arthritis patients.

Methods: Nineteen autoantibody-positive individuals (IgM-rheumatoid factor and/or anti-cyclic citrullinated peptide antibodies) with arthralgia (n=15) and/or a positive family history of RA (n=8), who had been prospectively followed for at least 2 years, were included. In addition, we included early arthritis patients (disease-modifying antirheumatic drug naïve) who after 2 years follow up fulfilled classification criteria for RA (n=63), spondyloarthritis (SpA; n=14), or had unclassified arthritis (UA; n=27). In all subjects we assessed pain and performed synovial biopsy sampling by mini-arthroscopy at baseline. Tissue sections were examined by immunohistochemistry to detect and quantify PGE2 pathway enzymes expression levels (mPGES-1; COX-1 and -2; 15-PGDH).

Results: In both study groups synovial expression of PGE2 enzymes was not clearly related to pain sensation. Expression levels at baseline were not associated with the development of arthritis after follow up (6 out of 19 autoantibody-positive individuals). However, in early SpA patients the expression levels of mPGES-1 and COX-1 were significantly increased compared to RA and UA patients.

Conclusion: Pain in autoantibody-positive individuals without synovial inflammation who are at risk of developing RA and in early arthritis patients may be regulated by pathways other than the PGE2 pathway or originate at sites other than the synovium. In contrast, in SpA, the PGE2 pathway may be inherently linked to the pathophysiology/etiology of the disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0133669PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520525PMC
May 2016

Intra-articular etanercept treatment in inflammatory arthritis: A randomized double-blind placebo-controlled proof of mechanism clinical trial validating TNF as a potential therapeutic target for local treatment.

Joint Bone Spine 2015 Oct 15;82(5):338-44. Epub 2015 Jul 15.

Arthrogen B.V., Meibergdreef 45, 1105 BA Amsterdam, The Netherlands; GlaxoSmithKline, Stevenage, UK; University of Cambridge, Cambridge, UK; Ghent University, Ghent, Belgium.

Objective: There is an increased interest in developing gene therapy approaches for local delivery of therapeutic genes in patients with arthritis. Intra-articular (i.a.) gene delivery, using an adeno-associated virus encoding a TNF soluble receptor, resulted in reduced paw swelling in an arthritis animal model, but i.a. treatment with a similar vector did not induce robust clinical improvement in patients. It is unclear whether this can be explained by for instance insufficient transduction efficiency or the fact that TNF is not a good therapeutic target for i.a treatment. The objective of this study was to explore the effects of i.a TNF blockade.

Methods: Thirty-one patients with rheumatoid or psoriatic arthritis were assigned to a single i.a. injection of 25mg etanercept or placebo in a double-blind randomised controlled clinical trial. The primary end point was target joint improvement, determined by a composite change index.

Results: Twenty-two patients received etanercept and 9 received placebo. Treatment was generally well tolerated. Treatment with etanercept resulted in a prompt and statistically significant improvement of the index (P<0.001) in comparison with placebo. As expected in light of the half-life of etanercept, the beneficial effect was transient and only statistically significant at week 1 and 2 after i.a. injection.

Conclusion: The results support the development of novel approaches for long-term inhibition of TNF at the site of inflammation, such as gene therapy.

Trial Registration: The Netherlands National Trial Register (NTR), www.trialregister.nl, NTR-1210.
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http://dx.doi.org/10.1016/j.jbspin.2015.03.002DOI Listing
October 2015

14-3-3η Autoantibodies: Diagnostic Use in Early Rheumatoid Arthritis.

J Rheumatol 2015 Sep 15;42(9):1587-94. Epub 2015 Jul 15.

From the Department of Medicine, University of Alberta, Edmonton, Alberta; Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Quebec; Mount Sinai Hospital, University of Toronto, Toronto; Augurex Life Sciences Corp., North Vancouver, British Columbia, Canada; Jan van Breemen Research Institute/Reade; VU University Medical Center; Academic Medical Center, Amsterdam; Division of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands; Hospital for Special Surgery, New York, New York, USA; University of Cambridge, Cambridge; GlaxoSmithKline Inc., Brentford, UK.W.P. Maksymowych, MD, Professor of Medicine, Department of Medicine, University of Alberta; G. Boire, MD, Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke; D. van Schaardenburg, MD, Jan van Breemen Research Institute/Reade; S. Wichuk, MD, Department of Medicine, University of Alberta; S. Turk, MD, Jan van Breemen Research Institute/Reade; M. Boers, MD, Professor of Clinical Epidemiology, VU University Medical Center; K.A. Siminovitch, MD, Professor of Medicine, Mount Sinai Hospital, University of Toronto; V. Bykerk, MD, Hospital for Special Surgery; E. Keystone, MD, Professor of Medicine, Mount Sinai Hospital, University of Toronto; P.P. Tak, MD, Academic Medical Center, and University of Cambridge, and GlaxoSmithKline Inc.; A.W. van Kuijk, MD; Robert Landewé, MD, Academic Medical Center; D. van der Heijde, MD, Division of Rheumatology, Leiden University Medical Center; M. Murphy, PhD; A. Marotta, PhD, Augurex Life Sciences Corp.

Objective: To describe the expression and diagnostic use of 14-3-3η autoantibodies in early rheumatoid arthritis (RA).

Methods: 14-3-3η autoantibody levels were measured using an electrochemiluminescent multiplexed assay in 500 subjects (114 disease-modifying antirheumatic drug-naive patients with early RA, 135 with established RA, 55 healthy, 70 autoimmune, and 126 other non-RA arthropathy controls). 14-3-3η protein levels were determined in an earlier analysis. Two-tailed Student t tests and Mann-Whitney U tests compared differences among groups. Receiver-operator characteristic (ROC) curves were generated and diagnostic performance was estimated by area under the curve (AUC), as well as specificity, sensitivity, and likelihood ratios (LR) for optimal cutoffs.

Results: Median serum 14-3-3η autoantibody concentrations were significantly higher (p < 0.0001) in patients with early RA (525 U/ml) when compared with healthy controls (235 U/ml), disease controls (274 U/ml), autoimmune disease controls (274 U/ml), patients with osteoarthritis (259 U/ml), and all controls (265 U/ml). ROC curve analysis comparing early RA with healthy controls demonstrated a significant (p < 0.0001) AUC of 0.90 (95% CI 0.85-0.95). At an optimal cutoff of ≥ 380 U/ml, the ROC curve yielded a sensitivity of 73%, a specificity of 91%, and a positive LR of 8.0. Adding 14-3-3η autoantibodies to 14-3-3η protein positivity enhanced the identification of patients with early RA from 59% to 90%; addition of 14-3-3η autoantibodies to anticitrullinated protein antibodies (ACPA) and/or rheumatoid factor (RF) increased identification from 72% to 92%. Seventy-two percent of RF- and ACPA-seronegative patients were positive for 14-3-3η autoantibodies.

Conclusion: 14-3-3η autoantibodies, alone and in combination with the 14-3-3η protein, RF, and/or ACPA identified most patients with early RA.
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http://dx.doi.org/10.3899/jrheum.141385DOI Listing
September 2015

Safety, Biodistribution, and Efficacy of an AAV-5 Vector Encoding Human Interferon-Beta (ART-I02) Delivered via Intra-Articular Injection in Rhesus Monkeys with Collagen-Induced Arthritis.

Hum Gene Ther Clin Dev 2015 Jun;26(2):103-12

1 Arthrogen B.V., Amsterdam 1105 BA, The Netherlands .

Preclinical studies to assess biodistribution, safety, and initial efficacy of ART-I02, an adeno-associated type 5 (rAAV5) vector expressing human interferon β (hIFN-β), were performed in a total of 24 rhesus monkeys with collagen-induced arthritis. All monkeys were naïve or showed limited neutralizing antibody (Nab) titers to AAV5 at the start of the study. Animals were injected with a single intra-articular dose of ART-I02 or placebo, consisting of 3.2×10(13) vg (Dose A=maximum feasible dose), 4.58×10(12) vg (Dose B), or placebo in the first affected finger joint, the ipsilateral knee, and ankle joint at the same time point. Animals were monitored for clinical parameters and well-being with a maximum of 4 weeks, with the option that the severity of arthritis could necessitate an earlier time point of sacrifice. No adverse events were noted after injection of ART-I02. No abnormalities were observed after histological evaluation of all organs. At both dose levels, immunohistochemical staining indicated expression of hIFN-β. In animals injected with Dose A, we observed stabilization or a reduction in swelling in the finger joint in which vector was administered. The highest copy numbers of vector DNA were detected in synovial tissue of the injected joint and the draining lymph node of the injected knee. High titers of Nab to rAAV5 were observed at the end of the study. Five monkeys developed an rAAV5-specific T-cell response. Two monkeys developed Nab to hIFN-β. In conclusion, intra-articular injection of ART-I02 was well-tolerated and did not induce adverse events. After administration of Dose A of ART-I02, we observed a beneficial effect on joint swelling, substantiated by decreased histological inflammation and bone erosion scores. A GMP vector for clinical application has been manufactured and is currently being tested in GLP rodent studies, with the aim to move forward to a clinical trial.
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http://dx.doi.org/10.1089/humc.2015.009DOI Listing
June 2015

Evaluation of Minimally Invasive, Ultrasound-guided Synovial Biopsy Techniques by the OMERACT Filter--Determining Validation Requirements.

J Rheumatol 2016 Jan 1;43(1):208-13. Epub 2015 Jun 1.

From the Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute at Barts, and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; Rheumatology and Translational Immunology Research Laboratories (LaRIT), Division of Rheumatology, IRCCS Policlinico San Matteo Foundation/University of Pavia, Pavia, Italy; Rheumatology Research Group, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK; Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, and Rheumatology Department, Lisbon Academic Medical Centre, Lisbon, Portugal; Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain and Department of Rheumatology, Cliniques Universitaires Saint-Luc, Brussels, Belgium; Rheumatology Department, Ambroise Paré Hospital, APHP, Université Versailles Saint Quentin en Yvelines, Inserm U987, Boulogne-Billancourt, France; Rheumatology Department, Hospital Universitario Severo Ochoa, Madrid, Spain; Laboratory for Skeletal Development and Joint Disorders, Department of Development and Regeneration, KU Leuven, Leuven, Belgium; University of Cambridge, Cambridge, UK; GlaxoSmithKline Research and Development, Stevenage, UK; School of Medicine and Medical Science, St. Vincent's University Hospital, Dublin, Ireland; Rheumatology Research Unit, Repatriation General Hospital, Daw Park, South Australia; Dublin Academic Medical Centre, The Conway Institute of Biomedical and Biomolecular Research, University College Dublin, Dublin, Ireland; Cardiff Institute of Infection and Immunity, Cardiff Regional Experimental Arthritis Treatment and Evaluation Centre, Cardiff, UK; Division of Immunology/Rheumatology, Stanford University School of Medicine, Stanford, California, USA.F. Humby, MRCP; S. Kelly, MRCP, Centre for Experimental Medicine and Rheumatology, William Harvey Research Ins

Objective: Because limited data currently support the clinical utility of peripherally expressed biomarkers in guiding treatment decisions for patients with rheumatoid arthritis, the search has turned to the disease tissue. The strategic aim of the Outcome Measures in Rheumatology (OMERACT) synovitis working group over the years has been to develop novel diagnostic and prognostic synovial biomarkers. A critical step in this process is to refine and validate minimally invasive, technically simple, robust techniques to sample synovial tissue, for use both in clinical trials and routine clinical practice. The objective of the synovitis working group (SWG) at OMERACT 12 (2014) was to examine whether recently developed ultrasound (US)-guided synovial biopsy techniques could be validated according to the OMERACT filter for future clinical use recommendation.

Methods: The SWG examined whether current data reporting US-guided synovial biopsy of both large and small joints addressed the OMERACT filters of truth, discrimination, and feasibility.

Results: There are currently limited data examining the performance of US-guided synovial biopsy, mainly from observational studies. Thus, it remains critical to evaluate its performance, within the clinical trials context, against the current gold standard of arthroscopic biopsy, with particular reference to: (1) synovial tissue yield, (2) capacity to determine treatment response as measured by a validated synovial biomarker, and (3) tolerability of the procedure.

Conclusion: We summarize the discrete work packages agreed to as requirements to validate US-guided synovial biopsy and therefore lead to a global consensus on the use of synovial biopsy for research and clinical practice.
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http://dx.doi.org/10.3899/jrheum.141199DOI Listing
January 2016

Neurostimulation of the cholinergic anti-inflammatory pathway ameliorates disease in rat collagen-induced arthritis.

PLoS One 2014 11;9(8):e104530. Epub 2014 Aug 11.

Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands; GlaxoSmithKline, Stevenage, United Kingdom; University of Cambridge, Cambridge, United Kingdom.

Introduction: The inflammatory reflex is a physiological mechanism through which the nervous system maintains immunologic homeostasis by modulating innate and adaptive immunity. We postulated that the reflex might be harnessed therapeutically to reduce pathological levels of inflammation in rheumatoid arthritis by activating its prototypical efferent arm, termed the cholinergic anti-inflammatory pathway. To explore this, we determined whether electrical neurostimulation of the cholinergic anti-inflammatory pathway reduced disease severity in the collagen-induced arthritis model.

Methods: Rats implanted with vagus nerve cuff electrodes had collagen-induced arthritis induced and were followed for 15 days. Animals underwent active or sham electrical stimulation once daily from day 9 through the conclusion of the study. Joint swelling, histology, and levels of cytokines and bone metabolism mediators were assessed.

Results: Compared with sham treatment, active neurostimulation of the cholinergic anti-inflammatory pathway resulted in a 52% reduction in ankle diameter (p = 0.02), a 57% reduction in ankle diameter (area under curve; p = 0.02) and 46% reduction overall histological arthritis score (p = 0.01) with significant improvements in inflammation, pannus formation, cartilage destruction, and bone erosion (p = 0.02), accompanied by numerical reductions in systemic cytokine levels, not reaching statistical significance. Bone erosion improvement was associated with a decrease in serum levels of receptor activator of NF-κB ligand (RANKL) from 132±13 to 6±2 pg/mL (mean±SEM, p = 0.01).

Conclusions: The severity of collagen-induced arthritis is reduced by neurostimulation of the cholinergic anti-inflammatory pathway delivered using an implanted electrical vagus nerve stimulation cuff electrode, and supports the rationale for testing this approach in human inflammatory disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0104530PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128811PMC
April 2015

Intrinsic healing response of the human anterior cruciate ligament: an histological study of reattached ACL remnants.

J Orthop Res 2014 Feb 5;32(2):296-301. Epub 2013 Nov 5.

A reattachment of the tibial remnant of the torn anterior cruciate ligament (ACL) to the posterior cruciate ligament is sometimes observed during surgery and apparently implies that the human ACL does have a healing response. The aim of this study was to investigate whether this reattachment tissue has similar histological characteristics of a healing response as the medial collateral ligament (MCL), which can heal spontaneously. Standard histology and immunostaining of α-smooth muscle actin and collagen type 3 was performed. The results shows that the reattached tissue has typical characteristics of a healing response: there attached ACL remnant could not be released by forceful traction; microscopy showed that the collagen fibers of the reattached tissue were disorganized with no preferred direction; increased neovascularization; the presence of lipid vacuoles; the mean number of cells within the biopsy tissue was 631±269 cells per mm2; and 68±20% was expressing α-SMA; semi-quantitative analysis of collagen type 3 expression showed that collagen type 3 had an high expression with an average score of 3. In conclusion, this study shows that the human proximal 1/3 ACL has an intrinsic healing response with typical histological characteristics similar to the MCL.
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http://dx.doi.org/10.1002/jor.22511DOI Listing
February 2014

FMS-related tyrosine kinase 3 ligand (Flt3L)/CD135 axis in rheumatoid arthritis.

Arthritis Res Ther 2013 ;15(6):R209

Introduction: The FMS-related tyrosine kinase 3 ligand (Flt3L)/CD135 axis plays a fundamental role in proliferation and differentiation of dendritic cells (DCs). As DCs play an important role in rheumatoid arthritis (RA) immunopathology we studied in detail the Flt3L/CD135 axis in RA patients.

Methods: The levels of Flt3L in (paired) serum and synovial fluid (SF) were quantified by enzyme-link immunosorbent assay (ELISA). Expression of Flt3L and CD135 in paired peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) was quantified by fluorescence-activated cell sorting (FACS). The expression of Flt3L, CD135 and TNF-Converting Enzyme (TACE) in synovial tissues (STs) and in vitro polarized macrophages and monocyte-derived DCs (Mo-DCs) was assessed by quantitative PCR (qPCR). CD135 ST expression was evaluated by immunohistochemistry and TACE ST expression was assessed by immunofluorescence. Flt3L serum levels were assessed in RA patients treated with oral prednisolone or adalimumab.

Results: Flt3L levels in RA serum, SF and ST were significantly elevated compared to gout patients and healthy individuals (HI). RA SF monocytes, natural killer cells and DCs expressed high levels of Flt3L and CD135 compared to HI. RA ST CD68+ and CD163+ macrophages, CD55+ fibroblast-like synoviocytes (FLS), CD31+ endothelial cells or infiltrating monocytes and CD19+ B cells co-expressed TACE. IFN-γ-differentiated macrophages expressed higher levels of Flt3L compared to other polarized macrophages. Importantly, Flt3L serum levels were reduced by effective therapy.

Conclusions: The Flt3L/CD135 axis is active in RA patients and is responsive to both prednisolone and adalimumab treatment. Conceivably, this ligand receptor pair represents a novel therapeutic target.
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http://dx.doi.org/10.1186/ar4403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978611PMC
November 2014

Genome-wide association study and gene expression analysis identifies CD84 as a predictor of response to etanercept therapy in rheumatoid arthritis.

PLoS Genet 2013 Mar 28;9(3):e1003394. Epub 2013 Mar 28.

Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8 × 10(-8)), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3' UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1 × 10(-11) in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry.
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http://dx.doi.org/10.1371/journal.pgen.1003394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3610685PMC
March 2013

The role of B lymphocytes in the progression from autoimmunity to autoimmune disease.

Clin Immunol 2013 Jan 22;146(1):34-45. Epub 2012 Oct 22.

Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, The Netherlands.

Autoimmunity, defined as the presence of autoreactive T and/or B lymphocytes in the periphery, is a frequent and probably even physiological condition. It is mainly caused by the fact that the central tolerance mechanisms, which are responsible for counter-selection of autoreactive lymphocytes, are not perfect and thus a limited number of these autoreactive cells can mature and enter the periphery. Nonetheless, autoreactive cells do not lead automatically to autoimmune disease as evidenced by a multitude of experimental and human data sets. Interestingly, the progression from autoimmunity to autoimmune disease is not only determined by the degree of central tolerance leakage and thus the amount of autoreactive lymphocytes in the periphery, but also by peripheral mechanism of activation and control of the autoreactive cells. In this review, we discuss the contribution of peripheral B lymphocytes in this process, ranging from activation of T cells and epitope spreading to control of the autoimmune process by regulatory mechanisms. We also discuss the parallels with the role of B cells in the induction and control of alloimmunity in the context of organ transplantation, as more precise knowledge of the pathogenic antigens and time of initiation of the immune response in allo- versus auto-immunity allows better dissection of the exact role of B cells. Since peripheral mechanisms may be easier to modulate than central tolerance, a more thorough understanding of the role of peripheral B cells in the progression from autoimmunity to autoimmune disease may open new avenues for treatment and prevention of autoimmune disorders.
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http://dx.doi.org/10.1016/j.clim.2012.10.005DOI Listing
January 2013

MicroRNAs--novel regulators of systemic lupus erythematosus pathogenesis.

Nat Rev Rheumatol 2012 Dec 16;8(12):701-9. Epub 2012 Oct 16.

Joint Molecular Rheumatology Laboratory of the Institute of Health Sciences and Shanghai Renji Hospital, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiaotong University School of Medicine, 145 Shan Dong Middle Road, Shanghai 200001, China.

Dysregulation of gene expression can cause complex disease phenotypes. MicroRNAs (miRNAs) are well known to fine-tune cellular gene expression to control immune cell development and regulate adaptive and innate immune responses. Discoveries over the past decade have indicated that aberrant expression of miRNAs is associated with the pathogenesis of multiple immunological diseases, including systemic lupus erythematosus (SLE). Indeed, profiling miRNA expression in blood cells, body fluid and target tissues taken from patients with SLE has revealed unique miRNA signatures when compared with healthy individuals or those with other diseases. Moreover, dysregulation of these miRNAs has also been found to be associated with disease activity and major organ involvement. In our opinion, therefore, miRNAs have the potential to act as biomarkers for the diagnosis and assessment of patients with SLE. This Review provides an overview of the novel cellular and molecular mechanisms that seem to underlie the roles of miRNAs in SLE disease processes, as well as the future therapeutic potential of targeting miRNAs in the management of patients with SLE.
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http://dx.doi.org/10.1038/nrrheum.2012.142DOI Listing
December 2012

Altered BANK1 expression is not associated with humoral autoimmunity in chronic joint inflammation.

Rheumatology (Oxford) 2013 Feb 11;52(2):252-60. Epub 2012 Oct 11.

Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.

Objective: The presence of disease-specific autoantibodies in RA but not spondyloarthritis (SpA) suggests that B-cell tolerance is preserved in the latter condition despite chronic joint inflammation. Which factors control B-cell tolerance vs autoimmunity in chronic arthritis remains incompletely understood. As single nucleotide polymorphisms in the B-cell scaffold protein with ankyrin repeats (BANK1) gene have recently been associated with various autoantibody-positive autoimmune diseases including RA, we explored whether altered expression of BANK1 was associated with humoral autoimmunity in arthritis.

Methods: Peripheral B-cell subsets and inflamed synovial tissue were obtained from active SpA and RA. Quantitative PCR was used to assess the expression of full-length BANK1 and delta2 BANK1, a splice variant lacking exon 2 that counteracts BANK1 function. B-cell subsets, autoantibody titres and clinical disease were monitored upon CIA induction in Bank1 knockout (KO) mice.

Results: Whereas full-length BANK1 was not differentially expressed, the BANK1 delta2 splicing variant was decreased in naïve peripheral B cells as well as in synovial tissue of SpA compared with RA. However, no differences were observed in seropositive vs seronegative RA. Performing functional analysis in mice, we found no differences in B-cell subsets and anti-collagen antibodies upon CIA induction between Bank1 KO mice and littermate controls. Accordingly, the incidence and severity of clinical disease were not altered in Bank1 KO mice.

Conclusion: This study did not reveal a major role for BANK1 in humoral autoimmunity in chronic arthritis. The decreased levels of BANK1 delta2 in SpA, however, warrant more detailed analysis of the functional consequences of an altered BANK1/BANK1 delta2 balance.
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http://dx.doi.org/10.1093/rheumatology/kes247DOI Listing
February 2013
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