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Spinal Diseases: HELP
Articles by Paul Peter Tak
Based on 53 articles published since 2009
(Why 53 articles?)
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Between 2009 and 2019, P. Tak wrote the following 53 articles about Spinal Diseases.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Guideline European League Against Rheumatism recommendations for the management of psoriatic arthritis with pharmacological therapies. 2012

Gossec, L / Smolen, J S / Gaujoux-Viala, C / Ash, Z / Marzo-Ortega, H / van der Heijde, D / FitzGerald, O / Aletaha, D / Balint, P / Boumpas, D / Braun, J / Breedveld, F C / Burmester, G / Cañete, J D / de Wit, M / Dagfinrud, H / de Vlam, K / Dougados, M / Helliwell, P / Kavanaugh, A / Kvien, T K / Landewé, R / Luger, T / Maccarone, M / McGonagle, D / McHugh, N / McInnes, I B / Ritchlin, C / Sieper, J / Tak, P P / Valesini, G / Vencovsky, J / Winthrop, K L / Zink, A / Emery, P / Anonymous2420706. ·Paris Descartes University, Paris, France. laure.gossec@cch.aphp.fr ·Ann Rheum Dis · Pubmed #21953336.

ABSTRACT: BACKGROUND: Psoriatic arthritis (PsA) is a clinically heterogeneous disease. Clear consensual treatment guidance focused on the musculoskeletal manifestations of PsA would be advantageous. The authors present European League Against Rheumatism (EULAR) recommendations for the treatment of PsA with systemic or local (non-topical) symptomatic and disease-modifying antirheumatic drugs (DMARD). METHODS: The recommendations are based on evidence from systematic literature reviews performed for non-steroidal anti-inflammatory drugs (NSAID), glucocorticoids, synthetic DMARD and biological DMARD. This evidence was discussed, summarised and recommendations were formulated by a task force comprising 35 representatives, and providing levels of evidence, strength of recommendations and levels of agreement. RESULTS: Ten recommendations were developed for treatment from NSAID through synthetic DMARD to biological agents, accounting for articular and extra-articular manifestations of PsA. Five overarching principles and a research agenda were defined. CONCLUSION: These recommendations are intended to provide rheumatologists, patients and other stakeholders with a consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes, based on combining evidence and expert opinion. The research agenda informs directions within EULAR and other communities interested in PsA.

2 Review Pathogenesis of spondyloarthritis: autoimmune or autoinflammatory? 2012

Ambarus, Carmen / Yeremenko, Nataliya / Tak, Paul P / Baeten, Dominique. ·Department of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands. ·Curr Opin Rheumatol · Pubmed #22488076.

ABSTRACT: PURPOSE OF REVIEW: Spondyloarthritis (SpA) is a chronic immune-mediated inflammatory disease of unknown origin. Here we aim to review whether SpA is driven by T-cell and/or B-cell autoreactivity or by abnormal innate immune responses. RECENT FINDINGS: SpA does not share genetic risk factors, female predominance, presence of disease-specific autoantibodies and response to T-cell or B-cell-targeted therapies with prototypical autoimmune diseases like rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Growing evidence indicates that increased responsiveness of innate immune cells such as macrophages, mast cells and neutrophils drives inflammation in SpA. The altered innate immune response may be related to nonantigen-presenting functions of HLA-B27, including the induction of an unfolded protein response, and can be triggered by bacterial and mechanical stress. Innate immune cells appear to be the main producers of both pro-inflammatory (tumor necrosis factor, IL-1, IL-23, IL-17) and anti-inflammatory (IL-10) cytokines in SpA. SUMMARY: The predominance of myeloid above lymphoid alterations suggests an autoinflammatory rather than autoimmune origin of inflammation in SpA. Therefore, targeting innate cells or their inflammatory mediators may be more effective than T-cell or B-cell-directed therapies.

3 Review Advances in rheumatology: new targeted therapeutics. 2011

Tak, Paul P / Kalden, Joachim R. ·Department of Medicine, Division of Clinical Immunology and Rheumatology F4-105, Academic Medical Center/University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. P.P.Tak@amc.uva.nl ·Arthritis Res Ther · Pubmed #21624184.

ABSTRACT: Treatment of inflammatory arthritides - including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis - has seen much progress in recent years, partially due to increased understanding of the pathogenesis of these diseases at the cellular and molecular levels. These conditions share some common mechanisms. Biologic therapies have provided a clear advance in the treatment of rheumatological conditions. Currently available TNF-targeting biologic agents that are licensed for at east one of the above-named diseases are etanercept, infliximab, adalimumab, golimumab, and certolizumab. Biologic agents with a different mechanism of action have also been approved in rheumatoid arthritis (rituximab, abatacept, and tocilizumab). Although these biologic agents are highly effective, there is a need for improved management strategies. There is also a need for education of family physicians and other healthcare professionals in the identification of early symptoms of inflammatory arthritides and the importance of early referral to rheumatologists for diagnosis and treatment. Also, researchers are developing molecules - for example, the Janus kinase inhibitor CP-690550 (tofacitinib) and the spleen tyrosine kinase inhibitor R788 (fostamatinib) - to target other aspects of the inflammatory cascade. Initial trial results with new agents are promising, and, in time, head-to-head trials will establish the best treatment options for patients. The key challenge is identifying how best to integrate these new, advanced therapies into daily practice.

4 Review Synovitis in psoriatic arthritis: immunohistochemistry, comparisons with rheumatoid arthritis, and effects of therapy. 2011

van Kuijk, Arno W R / Tak, Paul P. ·Department of Rheumatology, Jan van Breemen Institute, Amsterdam, The Netherlands. a.w.vankuijk@amc.uva.nl ·Curr Rheumatol Rep · Pubmed #21503693.

ABSTRACT: Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy associated with psoriasis that affects the peripheral joints, spine, and entheses. Most patients with PsA present with peripheral synovitis of the oligoarticular or polyarticular subtype. As one of the targets of this disease, studies on the synovium may provide insight into the mechanisms involved in this condition. Key findings from the available studies comparing synovial tissue of PsA and rheumatoid arthritis patients are discussed in this review. Also, changes in the synovial infiltrate, expression of proinflammatory cytokines and adhesion molecules, and vascularity in synovial tissue after treatment with various medications are addressed. Finally, a model for proof-of-principle study design using serial synovial biopsies is described, which could be used to predict clinical (in)efficacy in early clinical trial design in PsA.

5 Review 'MRI-tis' in the early diagnosis of axial SpA: issues and limitations. 2010

De Rycke, Leen / Maas, Mario / Tak, Paul P / Baeten, Dominique. ·Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. ·Nat Rev Rheumatol · Pubmed #20924412.

ABSTRACT: Sacroiliitis on conventional radiography, a key diagnostic feature of axial spondyloarthritis (SpA), often appears only late in the disease course. With the introduction of potent biologic agents that may also be effective in early disease, diagnostic techniques that can identify SpA early in the disease course would be highly beneficial to patients. MRI has been proposed as a novel diagnostic tool for early axial SpA based on the visualization of active inflammatory lesions in established axial SpA, as well as in pre-radiographic axial SpA. Accordingly, MRI is already widely used in clinical practice and has been included in new classification criteria. However, the specificity and predictive value of MRI lesions for the development of axial SpA remain to be fully defined and validated. Most data come from cross-sectional analyses and have not been validated in prospective studies, and the few available prospective studies were performed in highly selected patient populations and have assessed the value of MRI for the prediction of sacroiliitis rather than axial SpA. Also, some studies have indicated considerable diversity in the pattern and extent of MRI lesions, and suggest that many lesions are not specific for SpA. Prospective, longitudinal studies are needed to validate the utility of this new imaging modality for the diagnosis of axial SpA.

6 Review Mediators of structural remodeling in peripheral spondylarthritis. 2009

Vandooren, Bernard / Yeremenko, Nataliya / Noordenbos, Troy / Bras, Johannes / Tak, Paul P / Baeten, Dominique. ·Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. ·Arthritis Rheum · Pubmed #19950262.

ABSTRACT: -- No abstract --

7 Review Where the immune response meets the vessel wall. 2009

Bisoendial, R J / Stroes, E S G / Tak, P P. ·Department of Clinical Immunology and Rheumatology, University of Amsterdam, the Netherlands. r.j.bisoendial@amc.uva.nl ·Neth J Med · Pubmed #19767659.

ABSTRACT: Immune-mediated inflammatory diseases (IMIDs), including rheumatoid arthritis and spondyloarthritis, are associated with increased cardiovascular morbidity and mortality, independent of the established cardiovascular risk factors. The chronic inflammatory state, a hallmark of IMIDs, is considered to be a driving force for accelerated atherogenesis. Consequently, aggressive control of disease activity has been suggested to be instrumental for cardiovascular risk reduction. Specific guidelines for cardiovascular risk reduction in patients with IMIDs, particularly rheumatoid arthritis, are lacking, largely due to the absence of randomised clinical trial data. In this review, we focus on pathophysiology and observational evidence of cardiovascular risk in different prototypes of IMIDs.

8 Review Synovial and mucosal immunopathology in spondyloarthritis. 2009

Vandooren, Bernard / Tak, Paul P / Baeten, Dominique. ·Clinical Immunology and Rheumatology, University of Amsterdam, Amsterdam, The Netherlands. ·Adv Exp Med Biol · Pubmed #19731621.

ABSTRACT: Chronic inflammation ofmusculoskeletal structures is the most prominent disease manifestation of SpA. More specifically, the axial disease affects the spine, the sacroiliac joints and the hips. Peripheral disease includes peripheral arthritis, with a preference for asymmetrical inflammation ofjoints of the lower limbs and enthesitis, which is the presence of inflammation at the sites were ligaments and tendons attach to the bone. Additionally, SpA is often characterized by subclinical inflammation of the gut which partially resembles inflammatory bowel disease. Here, we will review the immunopathology of these different disease manifestations and relate them to clinical applications as well as emerging pathogenic concepts.

9 Clinical Trial Rheumatoid arthritis and psoriatic arthritis synovial fluids stimulate prolactin production by macrophages. 2017

Tang, Man Wai / Garcia, Samuel / Malvar Fernandez, Beatriz / Gerlag, Danielle M / Tak, Paul-Peter / Reedquist, Kris A. ·Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; m.w.tang@amc.uva.nl. · Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. · Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. · GlaxoSmithKline, Cambridge, United Kingdom. · GlaxoSmithKline, Stevenage, United Kingdom. · Department of Rheumatology, Ghent University, Ghent, Belgium; and. · Department of Rheumatology, University of Cambridge, Cambridge, United Kingdom. ·J Leukoc Biol · Pubmed #28642278.

ABSTRACT: 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,

10 Clinical Trial Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial. 2014

McInnes, Iain B / Sieper, Joachim / Braun, Jürgen / Emery, Paul / van der Heijde, Désirée / Isaacs, John D / Dahmen, Georg / Wollenhaupt, Jürgen / Schulze-Koops, Hendrik / Kogan, Joseph / Ma, Shenglin / Schumacher, Martin M / Bertolino, Arthur P / Hueber, Wolfgang / Tak, Paul P. ·Institute of Infection, Immunity and Inflammation, University of Glasgow, , Glasgow, UK. ·Ann Rheum Dis · Pubmed #23361084.

ABSTRACT: OBJECTIVE: To evaluate the efficacy and safety of secukinumab, a fully human, anti-interleukin (IL)-17A monoclonal antibody, in patients with psoriatic arthritis (PsA). METHODS: 42 patients with active PsA fulfilling ClASsification for Psoriatic ARthritis (CASPAR) criteria were randomly assigned (2:1) to receive two intravenous secukinumab doses (10 mg/kg; n=28) or placebo (n=14) 3 weeks apart. The primary endpoint was the proportion of American College of Rheumatology (ACR) 20 responses at week 6 for secukinumab versus placebo (one-sided p<0.1). RESULTS: Primary endpoint: ACR20 responses at week 6 were 39% (9/23) for secukinumab versus 23% (3/13) for placebo (p=0.27). ACR20 responses were greater with secukinumab versus placebo at week 12 (39% (9/23) vs 15% (2/13), p=0.13) and week 24 (43% (10/23) vs 18% (2/11), p= 0.14). At week 6, 'good' European League Against Rheumatism response was seen in 21.7% (5/23) secukinumab versus 9.1% (1/11) placebo patients. Compared with placebo at week 6, significant reductions were observed among secukinumab recipients for C reactive protein (p=0.039), erythrocyte sedimentation rate (p=0.038), Health Assessment Questionnaire Disability Index (p=0.002) and Short Form Health Survey (SF-36; p=0.030) scores. The overall adverse event (AE) frequency was comparable between secukinumab (26 (93%)) and placebo (11 (79%)) recipients. Six serious AEs (SAEs) were reported in four secukinumab patients and one SAE in one placebo patient. CONCLUSIONS: Although the primary endpoint was not met, clinical responses, acute-phase reactant and quality of life improvements were greater with secukinumab versus placebo, suggesting some clinical benefit. Secukinumab exhibited satisfactory safety. Larger clinical trials of secukinumab in PsA are warranted.

11 Clinical Trial Anti-TNF treatment blocks the induction of T cell-dependent humoral responses. 2013

Salinas, Gabriela Franco / De Rycke, Leen / Barendregt, Barbara / Paramarta, Jacqueline E / Hreggvidsdottir, Hulda / Cantaert, Tineke / van der Burg, Mirjam / Tak, Paul P / Baeten, Dominique. ·Department of Clinical Immunology and Rheumatology, Academic Medical Centre/University of Amsterdam, Amsterdam, The Netherlands. ·Ann Rheum Dis · Pubmed #22968102.

ABSTRACT: OBJECTIVE: Experimental and human data suggest that tumour necrosis factor (TNF) blockade may affect B cell responses, in particular the induction of T cell-dependent (TD) humoral immunity. This study aimed to assess this hypothesis directly in patients with arthritis by analysing longitudinally the effect of TNF blockade on B cell activation and the maturation of humoral responses against TD and T cell-independent vaccines. MATERIALS AND METHODS: Peripheral blood samples were obtained from 56 spondyloarthritis patients before and after treatment with either non-steroidal anti-inflammatory drug (NSAID) alone or TNF blockers and analysed for B cell activation, plasma cell differentiation, germinal centre versus extra-follicular B cell maturation, and somatic hypermutation. Vaccine responses to hepatitis B and Streptococcus pneumoniae were measured by ELISA. RESULTS: TNF blockade augmented B cell activation as reflected by the expression of early activation markers, CD40, and costimulatory molecules, without affecting differentiation towards plasmablasts. This was associated with a specific increase of the unswitched fraction of circulating memory B cells and a decreased level of somatic hypermutation in anti-TNF treated patients, indicating an impairment of the germinal centre-dependent B cell maturation. In agreement with these findings, TNF blockade profoundly suppressed the response to the TD vaccination against hepatitis B, whereas the T cell-independent response against pneumococcal polysaccharides was only modestly affected. CONCLUSIONS: These data indicate that TNF blockade severely impedes the induction of primary TD humoral responses, probably by interfering with the germinal centre reaction.

12 Clinical Trial Expression of IL-20 in synovium and lesional skin of patients with psoriatic arthritis: differential response to alefacept treatment. 2012

Lebre, Maria C / Jonckheere, Christina L / Kraan, Maarten C / van Kuijk, Arno W R / Bos, Jan D / de Rie, Menno / Gerlag, Danielle M / Tak, Paul P. · ·Arthritis Res Ther · Pubmed #23006144.

ABSTRACT: INTRODUCTION: Psoriatic arthritis (PsA) is an inflammatory joint disease associated with psoriasis. Alefacept (a lymphocyte function-associated antigen (LFA)-3 Ig fusion protein that binds to CD2 and functions as an antagonist to T-cell activation) has been shown to result in improvement in psoriasis but has limited effectiveness in PsA. Interleukin-20 (IL-20) is a key proinflammatory cytokine involved in the pathogenesis of psoriasis. The effects of alefacept treatment on IL-20 expression in the synovium of patients with psoriasis and PsA are currently unknown. METHODS: Eleven patients with active PsA and chronic plaque psoriasis were treated with alefacept (7.5 mg per week for 12 weeks) in an open-label study. Skin biopsies were taken before and after 1 and 6 weeks, whereas synovial biopsies were obtained before and 4 and 12 weeks after treatment. Synovial biopsies from patients with rheumatoid arthritis (RA) (n = 10) were used as disease controls. Immunohistochemical analysis was performed to detect IL-20 expression, and stained synovial tissue sections were evaluated with digital image analysis. Double staining was performed with IL-20 and CD68 (macrophages), and conversely with CD55 (fibroblast-like synoviocytes, FLSs) to determine the phenotype of IL-20-positive cells in PsA synovium. IL-20 expression in skin sections (n = 6) was analyzed semiquantitatively. RESULTS: IL-20 was abundantly expressed in both PsA and RA synovial tissues. In inflamed PsA synovium, CD68+ macrophages and CD55+ FLSs coexpressed IL-20, and its expression correlated with the numbers of FLSs. IL-20 expression in lesional skin of PsA patients decreased significantly (P = 0.04) 6 weeks after treatment and correlated positively with the Psoriasis Area and Severity Index (PASI). IL-20 expression in PsA synovium was not affected by alefacept. CONCLUSIONS: Conceivably, the relatively limited effectiveness of alefacept in PsA patients (compared with anti-tumor necrosis factor (TNF) therapy) might be explained in part by persistent FLS-derived IL-20 expression.

13 Clinical Trial Change in CD3 positive T-cell expression in psoriatic arthritis synovium correlates with change in DAS28 and magnetic resonance imaging synovitis scores following initiation of biologic therapy--a single centre, open-label study. 2011

Pontifex, Eliza K / Gerlag, Danielle M / Gogarty, Martina / Vinkenoog, Marjolein / Gibbs, Adrian / Burgman, Ilse / Fearon, Ursula / Bresnihan, Barry / Tak, Paul Peter / Gibney, Robin G / Veale, Douglas J / FitzGerald, Oliver. ·Department of Rheumatology, St. Vincents University Hospital, Elm Park, Dublin 4, Ireland. elizapontifex@hotmail.com ·Arthritis Res Ther · Pubmed #21272347.

ABSTRACT: INTRODUCTION: With the development of increasing numbers of potential therapeutic agents in inflammatory disease comes the need for effective biomarkers to help screen for drug efficacy and optimal dosing regimens early in the clinical trial process. This need has been recognized by the Outcome Measures in Rheumatology Clinical Trials (OMERACT) group, which has established guidelines for biomarker validation. To seek a candidate synovial biomarker of treatment response in psoriatic arthritis (PsA), we determined whether changes in immunohistochemical markers of synovial inflammation correlate with changes in disease activity scores assessing 28 joints (ΔDAS28) or magnetic resonance imaging synovitis scores (ΔMRI) in patients with PsA treated with a biologic agent. METHODS: Twenty-five consecutive patients with PsA underwent arthroscopic synovial biopsies and MRI scans of an inflamed knee joint at baseline and 12 weeks after starting treatment with either anakinra (first 10 patients) or etanercept (subsequent 15 patients) in two sequential studies of identical design. DAS28 scores were measured at both time points. Immunohistochemical staining for CD3, CD68 and Factor VIII (FVIII) was performed on synovial samples and scored by digital image analysis (DIA). MRI scans performed at baseline and at 12 weeks were scored for synovitis semi-quantitatively. The ΔDAS28 of the European League Against Rheumatism good response definition (>1.2) was chosen to divide patients into responder and non-responder groups. Differences between groups (Mann Whitney U test) and correlations between ΔDAS28 with change in immunohistochemical and MRI synovitis scores (Spearman's rho test) were calculated. RESULTS: Paired synovial samples and MRI scans were available for 21 patients (8 anakinra, 13 etanercept) and 23 patients (8 anakinra, 15 etanercept) respectively. Change in CD3 (ΔCD3) and CD68 expression in the synovial sublining layer (ΔCD68sl) was significantly greater in the disease responders compared to non-responders following treatment (P = 0.005 and 0.013 respectively). ΔCD3, but not ΔCD68 or ΔFVIII, correlated with both ΔDAS28 (r = 0.49, P = 0.025) and ΔMRI (r = 0.58, P = 0.009). CONCLUSIONS: The correlation of ΔCD3 with ΔDAS28 and ΔMRI following biologic treatment in this cohort contributes to the validation of ΔCD3 as a synovial biomarker of disease response in PsA, and supports the further evaluation of ΔCD3 for predictive properties of future clinical outcomes.

14 Clinical Trial Abatacept in the treatment of patients with psoriatic arthritis: results of a six-month, multicenter, randomized, double-blind, placebo-controlled, phase II trial. 2011

Mease, Philip / Genovese, Mark C / Gladstein, Geoffrey / Kivitz, Alan J / Ritchlin, Christopher / Tak, Paul P / Wollenhaupt, Jürgen / Bahary, Orna / Becker, Jean-Claude / Kelly, Sheila / Sigal, Leonard / Teng, Julie / Gladman, Dafna. ·University of Washington, Seattle, WA, USA. pmease@nwlink.com ·Arthritis Rheum · Pubmed #21128258.

ABSTRACT: OBJECTIVE: To assess the safety and efficacy of abatacept, a selective T cell costimulation modulator, in patients with psoriatic arthritis (PsA). METHODS: In this 6-month, multicenter, randomized, double-blind, placebo-controlled, phase II study, 170 PsA patients with a psoriasis target lesion (TL) ≥2 cm who had previously taken disease-modifying antirheumatic drugs (DMARDs), including anti-tumor necrosis factor (anti-TNF) agents, were randomized (1:1:1:1) to receive placebo or abatacept at doses of 3 mg/kg, 10 mg/kg, or 30/10 mg/kg (2 initial doses of 30 mg/kg, followed by 10 mg/kg) on days 1, 15, and 29 and then once every 28 days thereafter. The primary end point was the American College of Rheumatology 20% criteria for improvement (ACR20 response) on day 169. Other key end points were magnetic resonance imaging (MRI) scores for joint erosion, osteitis, and synovitis, scores on the Health Assessment Questionnaire (HAQ) and the Short Form-36 (SF-36) health survey, the investigator's global assessment of psoriasis, the TL score, and the Psoriasis Area and Severity Index (PASI) score. RESULTS: Proportions of patients achieving an ACR20 response were 19%, 33%, 48%, and 42% in the placebo, the abatacept 3 mg/kg, the abatacept 10 mg/kg, and the abatacept 30/10 mg/kg groups, respectively. Compared with placebo, improvements were significantly higher for the abatacept 10 mg/kg (P = 0.006) and 30/10 mg/kg (P = 0.022) groups, but not for 3 mg/kg group (P = 0.121). All abatacept regimens resulted in improved MRI, HAQ, and SF-36 scores, with 10 mg/kg showing the greatest improvements. Improvements in the TL and PASI scores were observed in all abatacept arms; a response according to the investigator's global assessment was seen only with 3 mg/kg of abatacept. The safety profiles were similar among the treatment arms. CONCLUSION: The results of this study suggest that 10 mg/kg of abatacept, the approved dosage for rheumatoid arthritis and juvenile idiopathic arthritis, may be an effective treatment option for PsA.

15 Article MiR-146a G/C rs2910164 variation in South African Indian and Caucasian patients with psoriatic arthritis. 2018

Maharaj, Ajesh B / Naidoo, Pragalathan / Ghazi, Terisha / Abdul, Naeem S / Dhani, Shanel / Docrat, Taskeen F / Ramkaran, Prithiksha / Tak, Paul-Peter / de Vries, Niek / Chuturgoon, Anil A. ·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 Center, University of Amsterdam, Amsterdam, Netherlands. · 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. · 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. chutur@ukzn.ac.za. ·BMC Med Genet · Pubmed #29587639.

ABSTRACT: 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%).

16 Article The prolactin receptor is expressed in rheumatoid arthritis and psoriatic arthritis synovial tissue and contributes to macrophage activation. 2016

Tang, Man Wai / Reedquist, Kris A / Garcia, Samuel / Fernandez, Bea Malvar / Codullo, Veronica / Vieira-Sousa, Elsa / Goffin, Vincent / Reuwer, Anne Q / Twickler, Marcel T / Gerlag, Daniëlle M / Tak, Paul-Peter. ·Division of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands, m.w.tang@amc.uva.nl. · Department of Experimental Immunology, Academic Medical Center/University of Amsterdam, the Netherlands. · Division of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands. · Inserm, Inserm U1151, Institut Necker Enfants Malades, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. · Division of Vascular Medicine, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands. ·Rheumatology (Oxford) · Pubmed #27616146.

ABSTRACT: 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 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.

17 Article Reduced CLEC9A expression in synovial tissue of psoriatic arthritis patients after adalimumab therapy. 2016

Ramos, Maria I / Teunissen, Marcel B M / Helder, Boy / Aarrass, Saida / de Hair, Maria J H / van Kuijk, Arno W / Gerlag, Danielle M / Tak, Paul P / Lebre, Maria C. ·Clinical Immunology and Rheumatology Department Experimental Immunology Department. · Dermatology Department, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. · Clinical Immunology and Rheumatology Department. · Clinical Immunology and Rheumatology Department Experimental Immunology Department c.lebre@amc.uva.nl. ·Rheumatology (Oxford) · Pubmed #27179104.

ABSTRACT: OBJECTIVES: We aimed to investigate the early changes in expression of C-type lectin domain family 9, member A (CLEC9A), a C-type lectin that is specifically expressed by the CD141(+) dendritic cell subset that is involved in cross-presentation to CD8(+) T cells, by evaluating gene and/or protein expression in three different compartments [skin, synovial tissue (ST) and serum] after short-term adalimumab treatment in PsA patients compared with placebo. METHODS: Patients with active PsA and psoriasis were randomized to receive adalimumab or placebo for 4 weeks. Synovial and skin biopsies were obtained before and after 4 weeks of treatment and serum samples 4 weeks, 12 weeks and 1 year after treatment. Skin and serum from healthy donors were used as control. CLEC9A expression was assessed by immunohistochemistry, double immunofluorescence using terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick-end labelling (TUNEL), quantitative PCR and ELISA. RESULTS: CLEC9A expression was significantly higher in psoriatic skin compared with healthy donor. In psoriatic skin and PsA ST, CLEC9A(+) cells were in close proximity to TUNEL(+) cells. SF CLEC9A levels were significantly lower compared with paired PsA serum. Adalimumab treatment did not affect CLEC9A serum level and skin expression. However, ST CLEC9A protein expression was significantly decreased after adalimumab treatment compared with the placebo group while CLEC9A gene expression remained unchanged. There was a positive correlation between T cell numbers and ST CLEC9A protein expression. CD141(+) cell numbers and chemokine (C motif) receptor 1 expression were not affected with adalimumab treatment. CONCLUSION: Altogether, the present study suggests that the downregulation of synovial CLEC9A might be associated with a novel mechanism by which anti-TNF therapy might reduce CD8-mediated inflammation in PsA patients.

18 Article Dynamic Contrast-Enhanced Magnetic Resonance Imaging Using Pharmacokinetic Modeling: Initial Experience in Patients With Early Arthritis. 2016

Maijer, Karen I / van der Leij, Christiaan / de Hair, Maria J H / Tas, Sander W / Maas, Mario / Gerlag, Daniëlle M / Tak, Paul P / Lavini, Cristina. ·Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. ·Arthritis Rheumatol · Pubmed #26473331.

ABSTRACT: OBJECTIVE: Analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using pharmacokinetic modeling (PKM) provides quantitative measures that mirror microvessel integrity and can be used as an objective marker of the level of synovial inflammation. The aim of this study was to investigate the PKM parameters K(trans) , kep , and ve in a prospective cohort of disease-modifying antirheumatic drug (DMARD)-naive patients with early arthritis, and to validate the results by assessing their correlation with the number of synovial endothelial cells (ECs). METHODS: Forty-seven patients with early arthritis (arthritis duration <1 year, DMARD naive; comprising 14 patients with rheumatoid arthritis, 22 with unclassified arthritis, 6 with spondyloarthritis [SpA], and 5 with other arthritides) were included. At baseline, DCE-MRI was performed on an inflamed knee joint of each patient. These images were used to calculate the K(trans) (volume transfer constant between the plasma and extracellular extravascular space [EES]), the kep (transfer constant between the EES and plasma), and the ve (fractional volume of the EES). Second, markers of disease activity were collected. Finally, vascularity was evaluated by immunohistochemical analysis of synovial tissue samples obtained from the inflamed knee joints, using antibodies to detect von Willebrand factor (vWF), a marker of ECs. RESULTS: The 3 PKM parameters differed significantly between diagnostic groups at baseline, with the highest K(trans) value being observed in patients with SpA (median 0.050/minute, interquartile range [IQR] 0.041- 0.069). Furthermore, the K(trans) , kep , and ve values correlated significantly with markers of disease activity. Finally, the PKM parameters K(trans) and kep , but not ve , correlated significantly with synovial expression of vWF (r = 0.647, P = 0.004 for K(trans) ; r = 0.614, P = 0.007 for kep ; r = 0.398, P = 0.102 for ve ). CONCLUSION: These results suggest that the K(trans) , kep , and ve can be used to detect synovial inflammation in patients with early arthritis, and these PKM parameters may be helpful in differential diagnosis. This approach may also be useful in translational research analyzing tissue microcirculation and angiogenesis.

19 Article A clinically based protein discovery strategy to identify potential biomarkers of response to anti-TNF-α treatment of psoriatic arthritis. 2016

Collins, Emily S / Butt, Aisha Q / Gibson, David S / Dunn, Michael J / Fearon, Ursula / van Kuijk, Arno W / Gerlag, Danielle M / Pontifex, Eliza / Veale, Douglas J / Tak, Paul P / FitzGerald, Oliver / Pennington, Stephen R. ·School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland. · Department of Rheumatology, St Vincent's University Hospital, Elm Park, Dublin, Ireland. · Northern Ireland Centre for Stratified Medicine, University of Ulster, C-TRIC, Londonderry, UK. · Department of Clinical Immunology and Rheumatology, F4-105, Academic Medical Centre/University of Amsterdam, Amsterdam, The Netherlands. ·Proteomics Clin Appl · Pubmed #26108918.

ABSTRACT: PURPOSE: Psoriatic arthritis (PsA) can be treated using biologic therapies targeting biomolecules such as tumor necrosis factor alpha, interleukins (IL)-17 and IL-23. Although 70% PsA patients respond well to therapy, 30% patients show no or limited clinical improvement. Biomarkers that predict response to therapy would help to avoid unnecessary use of expensive biologics in nonresponding patients and enable alternative treatments to be explored. EXPERIMENTAL DESIGN: Patient synovial tissue samples from two clinical studies were analysed using difference in-gel electrophoresis-based proteomics to identify protein expression differences in response to anti-TNF-α treatment. Subsequent multiplexed MRM measurements were used to verify potential biomarkers. RESULTS: A total of 119 proteins were differentially expressed (p<0.05) in response to anti-TNF-α treatment and 25 proteins were differentially expressed (p<0.05) between "good responders" and "poor responders". From these differentially expressed proteins, MRM assays were developed for four proteins to explore their potential as treatment predictive biomarkers. CONCLUSION AND CLINICAL RELEVANCE: Gel-based proteomics strategy has demonstrated differential protein expression in synovial tissue of PsA patients, in response to anti-TNF-α treatment. Development of multiplex MRM assays to these differentially expressed proteins has the potential to predict response to therapy and allow alternative, more effective treatments to be explored sooner.

20 Article Discovery and confirmation of a protein biomarker panel with potential to predict response to biological therapy in psoriatic arthritis. 2016

Ademowo, Opeyemi S / Hernandez, Belinda / Collins, Emily / Rooney, Cathy / Fearon, Ursula / van Kuijk, Arno W / Tak, Paul-P / Gerlag, Danielle M / FitzGerald, Oliver / Pennington, Stephen R. ·UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland. · UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland UCD School of Mathematical Sciences, University College Dublin, Dublin, Ireland. · UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland Department of Rheumatology, St. Vincent's University Hospital Dublin, Dublin, Ireland. · Department of Clinical Immunology/Rheumatology, Academic Medical Centre/University of Amsterdam, Amsterdam, Netherlands. ·Ann Rheum Dis · Pubmed #25187158.

ABSTRACT: OBJECTIVE: Biological therapies, which include antitumour necrosis factor-α and T-cell inhibitors, are potentially effective treatments for psoriatic arthritis (PsA) but are costly and may induce a number of side effects. Response to treatment in PsA is variable and difficult to predict. Here, we sought to identify a panel of protein biomarkers that could be used to predict which patients diagnosed with PsA will respond to biologic treatment. METHODS: An integrated discovery to targeted proteomics approach was used to investigate the protein profiles of good and non-responders to biological treatments in patients with PsA. Reverse-phase liquid chromatography coupled to tandem mass spectrometry was used to generate protein profiles of synovial tissue obtained at baseline from 10 patients with PsA. Targeted proteomics using multiple reaction monitoring (MRM) was used to confirm and prevalidate a potential protein biomarker panel in 18 and 7 PsA patient samples, respectively. RESULTS: A panel of 107 proteins was selected, and targeted mass spectrometry MRM assays were successfully developed for 57 of the proteins. The 57 proteins include S100-A8, S100-A10, Ig kappa chain C fibrinogen-α and γ, haptoglobin, annexin A1 and A2, collagen alpha-2, vitronectin, and alpha-1 acid glycoprotein. The proteins were measured simultaneously and confirmed to be predictive of response to treatment with an area under the curve of 0.76. In a blinded study using a separate cohort of patients, the panel was able to predict response to treatment. CONCLUSIONS: The approach reported here and the initial data provide evidence that a multiplexed protein assay of a panel of biomarkers that predict response to treatment could be developed. TRIAL REGISTRATION NUMBER: ISRCTN23328456.

21 Article Expression of Prostaglandin E2 Enzymes in the Synovium of Arthralgia Patients at Risk of Developing Rheumatoid Arthritis and in Early Arthritis Patients. 2015

de Hair, Maria J H / Leclerc, Patrick / Newsum, Elize C / Maijer, Karen I / van de Sande, Marleen G H / Ramwadhdoebe, Tamara H / van Schaardenburg, Dirkjan / van Baarsen, Lisa G M / Korotkova, Marina / Gerlag, Danielle M / Tak, Paul-Peter / Jakobsson, Per-Johan. ·Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands. · Rheumatology research Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden. · Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands; Department of Experimental Immunology, Academic Medical Center/University of Amsterdam, Amsterdam, the Netherlands. · Department of Rheumatology, Reade, Amsterdam, The Netherlands. ·PLoS One · Pubmed #26225917.

ABSTRACT: 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.

22 Article 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. 2015

Aalbers, Caroline / Gerlag, Danielle / Vos, Koen / Vervoordeldonk, Margriet / Landewé, Robert / Tak, Paul Peter. ·Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; Arthrogen B.V., Meibergdreef 45, 1105 BA Amsterdam, The Netherlands. Electronic address: c.j.aalbers@amc.uva.nl. · Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. · Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; Department of rheumatology, Flevoziekenhuis, Hospitaalweg 1, 1315 RA Almere, The Netherlands. · Arthrogen B.V., Meibergdreef 45, 1105 BA Amsterdam, The Netherlands. · Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; Department of Rheumatology, Atrium Medical Center, Postbus 4446, 6401 CX Heerlen, The Netherlands. · Arthrogen B.V., Meibergdreef 45, 1105 BA Amsterdam, The Netherlands; GlaxoSmithKline, Stevenage, UK; University of Cambridge, Cambridge, UK; Ghent University, Ghent, Belgium. ·Joint Bone Spine · Pubmed #26188879.

ABSTRACT: 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.

23 Article Single-joint Assessment for the Evaluation of Intraarticular Treatment: Responsiveness and Discrimination of the Composite Change Index. 2015

Aalbers, Caroline J / Gerlag, Danielle M / Vervoordeldonk, Margriet J / Tak, Paul P / Landewé, Robert B. ·From the Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; Arthrogen B.V., Amsterdam; Department of Rheumatology, Atrium Medical Center, Heerlen, the Netherlands.C.J. Aalbers, MD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, and Arthrogen B.V.; D.M. Gerlag, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam; M.J. Vervoordeldonk, PhD, Arthrogen B.V.; P.P. Tak, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, and Arthrogen B.V., and GlaxoSmithKline, and University of Cambridge; R.B. Landewé, MD, PhD, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, and Department of Rheumatology, Atrium Medical Center. ·J Rheumatol · Pubmed #26178282.

ABSTRACT: OBJECTIVE: To investigate responsiveness, discrimination, and construct validity of a composite change index (CCI) for the assessment of single-joint involvement in inflammatory arthritis. METHODS: Evaluation of standardized response means (SRM), Guyatt effect size, and Spearman rank correlation coefficient in a randomized controlled trial investigating the effect of an intraarticular etanercept injection. RESULTS: The CCI showed a high SRM (1.68) and high Guyatt effect size (2.72). Both visual analog scale of pain and functionality had a moderate Guyatt effect size (2.06, 2.44) and high SRM (0.81, 0.97). CONCLUSION: This study supports the use of the CCI as a single-joint assessment after single-joint intervention. CLINICAL TRIAL REGISTRATION: NTR-1210.

24 Article Summary of Sensitivity and Specificity for Psoriatic Arthritis in a South African Cohort according to Classification Criteria. 2015

Maharaj, Ajesh B / Govender, Jayandran / Maharaj, Kasthurba / Rajkaran, Michelle / Tak, Paul P. ·From the Department of Internal Medicine, Prince Mshiyeni Memorial Hospital, Nelson R. Mandela School of Medicine, University of KwaZulu Natal, Durban, South Africa; and the Division of Clinical Immunology and Rheumatology, European League Against Rheumatism (EULAR) and Federation of Clinical Immunology Societies (FOCIS) Center of Excellence, Academic Medical Center/University of Amsterdam, University of Amsterdam, the Netherlands.A.B. Maharaj, MB, BS (Varanasi), H Dip Int Med(SA), FCP (SA), Certificate in Rheumatology (SA), Department of Internal Medicine, Prince Mshiyeni Memorial Hospital, Nelson R. Mandela School of Medicine, University of KwaZulu Natal, and Division of Clinical Immunology and Rheumatology, EULAR and FOCIS Center of Excellence, Academic Medical Center/University of Amsterdam; J. Govender, BSc (Hons)(UDW), MB, ChB (Medunsa); K. Maharaj, MB, ChB (Natal), FCP (SA); M. Rajkaran, MBChB (Wits), FCP(SA), Department of Internal Medicine, Prince Mshiyeni Memorial Hospital, Nelson R. Mandela School of Medicine, University of KwaZulu Natal; P.P. Tak, MD, PhD (UvA), Division of Clinical Immunology and Rheumatology, EULAR and FOCIS Center of Excellence, Academic Medical Center/University of Amsterdam. ·J Rheumatol · Pubmed #25877500.

ABSTRACT: OBJECTIVE: To evaluate the sensitivity and specificity of the classification criteria for psoriatic arthritis (PsA) in a South African cohort. METHODS: Data from consecutive patients with PsA and other chronic inflammatory arthritides were collected prospectively. Subjects were classified according to the classification criteria. The sensitivity and specificity in each group of patients were compared with a clinical diagnosis made by a rheumatologist. RESULTS: The European Spondylarthropathy Study Group criteria exhibited the lowest sensitivity followed by the Moll and Wright criteria. The sensitivity and specificity of the ClASsification for Psoriatic ARthritis (CASPAR) criteria were 98.4% and 99.7%, respectively. CONCLUSION: The CASPAR criteria were evaluated in our cohort and they performed well.

25 Article Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid arthritis. 2015

Greven, D E A / Cohen, E S / Gerlag, D M / Campbell, J / Woods, J / Davis, N / van Nieuwenhuijze, A / Lewis, A / Heasmen, S / McCourt, M / Corkill, D / Dodd, A / Elvin, J / Statache, G / Wicks, I P / Anderson, I K / Nash, A / Sleeman, M A / Tak, P P. ·Department of Clinical Immunology and Rheumatology, Academic Medical Center/ University of Amsterdam, Amsterdam, The Netherlands. · Department of Respiratory, Inflammation and AutoImmunity Research, MedImmune Limited, Cambridge, UK. · Department of Clinical Immunology and Rheumatology, Academic Medical Center/ University of Amsterdam, Amsterdam, The Netherlands GlaxoSmithKline, Cambridge, UK. · Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. · Department of Research and Development, CSL Limited, Parkville, Victoria, Australia. · Department of Clinical Immunology and Rheumatology, Academic Medical Center/ University of Amsterdam, Amsterdam, The Netherlands GlaxoSmithKline, Stevenage, UK University of Cambridge, Cambridge, UK. ·Ann Rheum Dis · Pubmed #24936585.

ABSTRACT: OBJECTIVE: Previous work has suggested that the granulocyte macrophage colony stimulating factor (GM-CSF)-GM-CSF receptor α axis (GM-CSFRα) may provide a new therapeutic target for the treatment of rheumatoid arthritis (RA). Therefore, we investigated the cellular expression of GM-CSFRα in RA synovial tissue and investigated the effects of anti-GM-CSFRα antibody treatment in vitro and in vivo in a preclinical model of RA. METHODS: We compared GM-CSFRα expression on macrophages positive for CD68 or CD163 on synovial biopsy samples from patients with RA or psoriatic arthritis (PsA) to disease controls. In addition, we studied the effects of CAM-3003, an anti-GM-CSFR antibody in a collagen induced arthritis model of RA in DBA/1 mice. The pharmacokinetic profile of CAM-3003 was studied in naïve CD1(ICR) mice (see online supplement) and used to interpret the results of the pharmacodynamic studies in BALB/c mice. RESULTS: GM-CSFRα was expressed by CD68 positive and CD163 positive macrophages in the synovium, and there was a significant increase in GM-CSFRα positive cells in patients in patients with RA as well as patients with PsA compared with patients with osteoarthritis and healthy controls. In the collagen induced arthritis model there was a dose dependent reduction of clinical arthritis scores and the number of F4/80 positive macrophages in the inflamed synovium after CAM-3003 treatment. In BALB/c mice CAM-3003 inhibited recombinant GM-CSF mediated margination of peripheral blood monocytes and neutrophils. CONCLUSIONS: The findings support the ongoing development of therapies aimed at interfering with GM-CSF or its receptor in various forms of arthritis, such as RA and PsA.

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