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1.  Early start and stop of biologics: has the time come? 
BMC Medicine  2014;12:25.
Despite considerable advances in the management of rheumatoid arthritis, results are still not satisfactory for all patients. The treatment goal in rheumatoid arthritis is remission, and there currently are numerous conventional and biological medications available to reach this aim. There are also different treatment strategies but with only limited comparative evidence about their efficacies. More patients now achieve remission while on treatment, but it remains elusive in the majority of patients. Treatment-free remission, the ultimate goal of therapy, is only achieved in very few patients; even when this happens, it is most likely due to the natural course of the disease rather than to any specific therapies. Modern treatment is based on the initiation of aggressive therapy as soon as the diagnosis is established, and on modifying or intensifying therapy guided by frequent assessment of disease activity. In this commentary we will discuss the current treatment paradigm as well as the possibility of an induction-maintenance regimen with biological disease-modifying antirheumatic drugs in early rheumatoid arthritis.
doi:10.1186/1741-7015-12-25
PMCID: PMC3915229  PMID: 24502187
Biologics; Rheumatoid arthritis; Treatment
2.  Safety with Ocrelizumab in Rheumatoid Arthritis: Results from the Ocrelizumab Phase III Program 
PLoS ONE  2014;9(2):e87379.
Objective
The objective was to determine the safety of ocrelizumab (OCR) in patients with rheumatoid arthritis (RA).
Methods
This was an analysis of the double-blind, placebo-controlled periods and long-term follow-up of 4 OCR phase III trials in RA (SCRIPT, STAGE, FILM and FEATURE). Safety data per study and the results of a meta-analysis of serious infectious events (SIEs) are presented.
Results
Overall, 868 patients received placebo, 1064 patients OCR 200 mg×2 (or 400 mg×1) (OCR200), and 827 patients OCR 500 mg×2 (OCR500) plus background methotrexate (MTX) at baseline and 24 weeks. During the double-blind, placebo-controlled periods, the incidence of adverse events and serious adverse events was comparable between the OCR+MTX and placebo +MTX groups. Infusion-related reactions were more common with OCR+MTX and decreased in frequency with subsequent infusions. Serious infusion-related reactions were rare (0.1%). Serious infections occurred more frequently with OCR500+MTX. In the meta-analysis, a statistically significant difference from placebo +MTX in incidence of SIEs per 100 patient-years of 2.4 (95% CI, 0.3–4.5) was observed with OCR500+MTX, but not with OCR200+MTX (0.6; 95% CI, −1.3 to 2.4). Patients recruited in Asia exhibited a higher risk of serious infections (hazard ratio, 1.78; 95% CI, 1.03–3.06). The incidence of human anti-human antibodies was <5%. Long-term follow-up indicated no differences in malignancy rates between the treatment groups. There was no apparent difference in time to B-cell repletion between the OCR dose groups.
Conclusions
In placebo-controlled clinical trials of RA, OCR500+MTX was associated with a higher risk of serious infections compared with placebo +MTX. The safety profile of OCR 200+MTX was comparable with placebo+MTX.
Trial Registration
STAGE Clinical Trials.gov NCT00406419
SCRIPT Clinical Trials.gov NCT00476996
FILM Clinical Trials.gov NCT00485589
FEATURE Clinical Trials.gov NCT00673920
doi:10.1371/journal.pone.0087379
PMCID: PMC3911947  PMID: 24498318
3.  Relationship between inflammation, bone destruction, and osteoproliferation in spondyloarthritis in HLA-B27/Huβ2m transgenic rats 
Arthritis and rheumatism  2012;64(10):3210-3219.
Objective
Inhibition of inflammation and destruction but not osteoproliferation in spondyloarthritis (SpA) patients treated with anti-TNF raises the question of how these three processes are interrelated. This study aimed to analyze this relationship in a SpA rat model.
Methods
Histological spine and joint samples of HLA-B27/Huβ2m transgenic rats were analyzed for signs of spondylitis and destructive arthritis and semi-quantitatively scored as mild, moderate or severe inflammation.
Results
In spondylitis, mild inflamed sections displayed lymphocyte infiltration in connective tissue adjacent to the junction of the annulus fibrosus and vertebral bone but not at the enthesis. Moderate inflamed tissue samples contained osteoclasts eroding bone outside the cartilage endplate. In severe inflammation, the cartilage endplate and underlying bone marrow were also affected. End-stage disease was characterized by complete destruction of the intervertebral disc and vertebrae, with ongoing infiltration. Osteoproliferation was not observed in samples with no or mild inflammation, but was present at the edge of the vertebrae in moderate inflammation and persisted during severe inflammation and end-stage destruction. Osteoproliferation occurred at the border of inflammation, at a distance from bone destruction. A strong correlation between the extent of inflammation, destruction and osteoproliferation was observed. Arthritis displayed a similar pattern of synovial inflammation associated with bone destruction, and simultaneous but topographically distinct osteoproliferation starting from the periosteum.
Conclusion
Spondyloarthritis in HLA-B27/Huβ2m tg rats is characterized by destructive inflammatory pannus tissue rather than by enthesitis or osteitis. Destruction and osteoproliferation occur simultaneously but at distinct sites in joints with moderate to severe inflammation.
doi:10.1002/art.34600
PMCID: PMC3462233  PMID: 22736144
4.  Prevalence and pharmacological modulation of humoral immunity to AAV vectors in gene transfer to synovial tissue 
Gene therapy  2012;20(4):417-424.
Antibodies against adeno-associated viral vectors (AAV) are highly prevalent in humans. Both preclinical and clinical studies showed that antibodies against AAV block transduction even at low titers, particularly when the vector is introduced into the bloodstream. Here we measured the neutralizing antibody (NAb) titer against AAV serotype 2, 5, 6, and 8 in serum and matched synovial fluid (SF) from rheumatoid arthritis patients. The titer in SF was lower than in the matched plasma samples, indicating a difference in distribution of NAb to AAV depending on the body fluid compartment. This difference was more evident for AAV2, against which higher titers were measured. Of all serotypes, anti-AAV5 antibodies were the least prevalent in both serum and SF. We next evaluated the impact on anti-AAV antibodies of B cell depletion in rheumatoid arthritis patients who received one or two courses of the anti-CD20 antibody rituximab as part of their disease management. A drop of NAb titer was observed in a subset of those subjects carrying NAb titers ≤1:1000, however only in a minority of subjects titers dropped below 1:5. This work provides insights into strategies to overcome the limitation of pre-existing humoral immunity to AAV vectors.
doi:10.1038/gt.2012.55
PMCID: PMC3473155  PMID: 22786533
adeno-associated virus vectors; neutralizing antibodies; synovial tissue
5.  The expression of APRIL in Sjögren’s syndrome: aberrant expression of APRIL in the salivary gland 
Rheumatology (Oxford, England)  2012;51(9):1557-1562.
Objective. A proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) are B-cell-related mediators and may play a role in the pathogenesis in SS. In this descriptive study we assessed the expression of APRIL and BAFF in the minor salivary gland and serum from SS patients.
Methods. Paraffin-embedded minor salivary gland sections from SS patients, non-SS controls and healthy volunteers were analysed by immunohistochemistry. Digital image quantification was performed to evaluate the expression of BAFF, APRIL and transmembrane activator and CAML interactor. Furthermore, serum was analysed for soluble BAFF and APRIL levels by ELISA. All the data were also analysed for subjects with decreased and normal stimulated salivary flow independent of the classification.
Results. APRIL expression was lower in minor salivary gland biopsies from SS patients compared with healthy volunteers and to a lesser extent non-SS controls, whereas BAFF expression was similar in all groups. Soluble APRIL levels in serum were increased in SS patients and in subjects with decreased salivary flow independent of the classification.
Conclusion. APRIL salivary gland tissue levels are decreased, suggesting that targeting this cytokine locally in the salivary glands would not benefit SS patients. Moreover, the discrepancy between local and systemic levels is striking and future research should assess this in more detail.
doi:10.1093/rheumatology/kes080
PMCID: PMC3418645  PMID: 22562936
Sjögren’s syndrome; minor salivary glands; a proliferation inducing ligand
6.  Interleukin 1 receptor antagonist mediates the beneficial effects of systemic interferon beta in mice: implications for rheumatoid arthritis 
Annals of the rheumatic diseases  2011;70(5):858-863.
Objectives
Interferon beta (IFNβ) therapy is effective in multiple sclerosis and murine models of arthritis. Surprisingly, systemic IFNβ treatment induces only minimal improvement in rheumatoid arthritis (RA). To explain this paradox, the authors evaluated the mechanism of IFNβ benefit in passive K/BxN arthritis and the effect of IFNβ treatment on RA synovium.
Methods
Interleukin 10 (IL-10) null, IL-1 receptor antagonist (IL-1Ra) null, IL-1Ra transgenic and wild-type mice were administered K/BxN serum and in some cases treated with IFNβ or normal saline. Clinical response and histological scores were assessed. Gene expression was measured by quantitative PCR. Serum IL-1Ra and IL-6 were measured by ELISA. Paired synovial biopsy specimens from RA patients pre-IFNβ and post-IFNβ treatment (purified natural fibroblast IFNβ (Frone) subcutaneously three times weekly 6 million IU, 12 million IU or 18 million IU) were immunostained for IL-1Ra and IL-10.
Results
Il1rn transgenic mice had an attenuated course of arthritis, whereas Il1rn−/− and Il10−/− mice had more severe serum transfer arthritis than wild-type mice. Daily IFNβ treatment significantly decreased arthritis severity in Il10−/− but not Il1rn−/− mice. IFNβ treatment did not reduce the histological scores in Il1rn−/− mice or gene expression of articular cytokines and chemokines. Paired synovial biopsy specimens from RA patients treated with IFNβ demonstrated a trend towards increased IL-1Ra and reduced IL-10 expression on day 85 levels compared with pretreatment specimens.
Conclusions
The anti-inflammatory effects of IFNβ in passive K/BxN arthritis are dependent on IL-1Ra, but not IL-10. Systemic IFNβ treatment in RA increases synovial IL-1Ra production, but also decreases IL-10 production.
doi:10.1136/ard.2010.141077
PMCID: PMC3728888  PMID: 21216819
7.  A personalized medicine approach to biologic treatment of rheumatoid arthritis: a preliminary treatment algorithm 
Rheumatology (Oxford, England)  2011;51(4):600-609.
RA is a syndrome consisting of different pathogenetic subsets in which distinct molecular mechanisms may drive common final pathways. Recent work has provided proof of principle that biomarkers may be identified predictive of the response to targeted therapy. Based on new insights, an initial treatment algorithm is presented that may be used to guide treatment decisions in patients who have failed one TNF inhibitor. Key questions in this algorithm relate to the question whether the patient is a primary vs a secondary non-responder to TNF blockade and whether the patient is RF and/or anti-citrullinated peptide antibody positive. This preliminary algorithm may contribute to more cost-effective treatment of RA, and provides the basis for more extensive algorithms when additional data become available.
doi:10.1093/rheumatology/ker300
PMCID: PMC3306168  PMID: 21890615
rheumatoid arthritis; treatment; biomarkers; biologicals
8.  Mycophenolate mofetil but not atorvastatin attenuates atherosclerosis in lupus-prone LDLr−/− mice 
Annals of the Rheumatic Diseases  2011;71(3):408-414.
Rationale
Recent clinical and preclinical studies have demonstrated that systemic lupus erythematosus (SLE) is associated with an increased risk for cardiovascular disease (CVD). However, unlike in the general population, little is known regarding the efficacy of atheroprotective interventions in patients with SLE. The current study aims to determine the benefit of lymphocyte inhibition on reducing the atherosclerotic burden in SLE-susceptible LDLr-deficient mice.
Methods
Female LDLr−/− mice were lethally irradiated and reconstituted with bone marrow from C57Bl/6 mice (LDLr.B6) or the SLE-susceptible B6.Sle1.2.3 mice (LDLr. Sle). At 16 weeks post transplant, mice were treated with atorvastatin (10 mg/kg), mycophenolate mofetil (MMF; 40 mg/kg), or both (MMF-A) for 8 weeks, after which the extent of atherosclerosis and the presence of SLE were assessed.
Results
Following 8 weeks of treatment, we observed that atorvastatin-mediated reduction in cholesterol levels attenuated atherogenesis in LDLr.B6 mice but failed to significantly reduce atherosclerotic lesion size in LDLr. Sle mice, in spite of a significant reduction in serum cholesterol levels. Treatment with MMF and MMF-A attenuated atherogenesis in LDLr.B6 and LDLr.Sle mice. In addition, MMF-containing regimens inhibited recruitment of CD4+ T cells to atherosclerotic lesions in LDLr.Sle mice. In these mice, MMF also reduced the proportion of activated splenic T cells, as well as interleukin 10 secretion by T cells. With regard to lupus activity, MMF had no overt effect on anti-double-stranded DNA (dsDNA) antibody titres or kidney function and pathology.
Conclusions
The current study demonstrates that reduction of cholesterol levels alone is not atheroprotective in lupus-mediated atherogenesis. This is the first study to demonstrate that MMF reduces the atherosclerotic burden in a model of lupus-accelerated atherosclerosis. Our results suggest that MMF treatment may prove beneficial in preventing CVD in patients with SLE.
doi:10.1136/annrheumdis-2011-200071
PMCID: PMC3306213  PMID: 21953346
9.  Lessons Learned from Synovial Tissue Analysis 
doi:10.2174/1874312901105010098
PMCID: PMC3263473  PMID: 22279507
10.  Microscopic measurement of inflammation in synovial tissue: inter‐observer agreement for manual quantitative, semiquantitative and computerised digital image analysis 
Annals of the Rheumatic Diseases  2007;66(12):1656-1660.
Objectives
To evaluate inter‐observer agreement for microscopic measurement of inflammation in synovial tissue using manual quantitative, semiquantitative and computerised digital image analysis.
Methods
Paired serial sections of synovial tissue, obtained at arthroscopic biopsy of the knee from patients with rheumatoid arthritis (RA), were stained immunohistochemically for T lymphocyte (CD3) and macrophage (CD68) markers. Manual quantitative and semiquantitative scores for sub‐lining layer CD3+ and CD68+ cell infiltration were independently derived in 6 international centres. Three centres derived scores using computerised digital image analysis. Inter‐observer agreement was evaluated using Spearman's Rho and intraclass correlation coefficients (ICCs).
Results
Paired tissue sections from 12 patients were selected for evaluation. Satisfactory inter‐observer agreement was demonstrated for all 3 methods of analysis. Using manual methods, ICCs for measurement of CD3+ and CD68+ cell infiltration were 0.73 and 0.73 for quantitative analysis and 0.83 and 0.78 for semiquantitative analysis, respectively. Corresponding ICCs of 0.79 and 0.58 were observed for the use of digital image analysis. All ICCs were significant at levels of p<0.0001. At each participating centre, use of computerised image analysis produced results that correlated strongly and significantly with those obtained using manual measurement.
Conclusion
Strong inter‐observer agreement was demonstrated for microscopic measurement of synovial inflammation in RA using manual quantitative, semiquantitative and computerised digital methods of analysis. This further supports the development of these methods as outcome measures in RA.
doi:10.1136/ard.2006.061143
PMCID: PMC2095312  PMID: 17604286
11.  Activated complement components and complement activator molecules on the surface of cell‐derived microparticles in patients with rheumatoid arthritis and healthy individuals 
Annals of the Rheumatic Diseases  2007;66(8):1085-1092.
Objectives
In vitro, microparticles can activate complement via the classical pathway. If demonstrable ex vivo, this mechanism may contribute to the pathogenesis of rheumatoid arthritis (RA). We therefore investigated the presence of activated complement components and complement activator molecules on the surface of cell‐derived microparticles of RA patients and healthy individuals.
Methods
Microparticles from synovial fluid (n = 8) and plasma (n = 9) of 10 RA patients and plasma of sex‐ and age‐matched healthy individuals (n = 10) were analysed by flow cytometry for bound complement components (C1q, C4, C3) and complement activator molecules (C‐reactive protein (CRP), serum amyloid P component (SAP), immunoglobulin (Ig) M, IgG).
Results
Microparticles with bound C1q, C4, and/or C3 were abundant in RA synovial fluid, while in RA and control plasma much lower levels were present. Microparticles with bound C1q correlated with those with bound C3 in synovial fluid (r = 0.961, p = 0.0001), and with those with bound C4 in plasma (RA: r = 0.908, p = 0.0007; control: r = 0.632, p = 0.0498), indicating classical pathway activation. In synovial fluid, microparticles with IgM and IgG correlated with those with C1q (r = 0.728, p = 0.0408; r = 0.952, p = 0.0003, respectively), and in plasma, microparticles with CRP correlated with those with C1q (RA: r = 0.903, p = 0.0021; control: r = 0.683, p = 0.0296), implicating IgG and IgM in the classical pathway activation in RA synovial fluid, and CRP in the low level classical pathway activation in plasma.
Conclusions
This study demonstrates the presence of bound complement components and activator molecules on microparticles ex vivo, and supports their role in low grade complement activation in plasma and increased complement activation in RA synovial fluid.
doi:10.1136/ard.2006.061309
PMCID: PMC1954699  PMID: 17261534
complement activation; microparticles; rheumatoid arthritis
12.  Local Administration of Soluble CD40:Fc to the Salivary Glands of Non-Obese Diabetic Mice Does Not Ameliorate Autoimmune Inflammation 
PLoS ONE  2012;7(12):e51375.
Objective
CD40–CD154 (CD40 ligand) interaction in the co-stimulatory pathway is involved in many (auto)immune processes and both molecules are upregulated in salivary glands of Sjögren’s syndrome (SS) patients. Interference within the CD40 pathway has ameliorated (auto)inflammation in a number of disease models. To test the potential role of the CD40 pathway in loss of gland function and inflammation in SS, an inhibitor of CD40-CD154 interaction was overexpressed in the salivary glands (SGs) of a spontaneous murine model of SS; the Non-Obese Diabetic (NOD) mouse.
Materials and Methods
At different disease stages an adeno associated viral vector encoding CD40 coupled to a human Fc domain (CD40:Fc) was injected locally into the SGs of NOD mice. Delivery was confirmed by PCR. The overall effect on local inflammation was determined by assessment of the focus score (FS), quantification of infiltrating cell types, immunoglobulin levels, and microarray analysis. The effect on SG function was determined by measuring stimulated salivary flow.
Results
CD40:Fc was stably expressed in the SG of NOD mice, and the protein was secreted into the blood stream. Microarray analysis revealed that expression of CD40:Fc affected the expression of many genes involved in regulation of the immune response. However, FS, infiltrating cell types, immunoglobulin levels, and salivary gland output were similar for treated and control mice.
Discussion
Although endogenous CD40 is expressed in SG inflammatory foci in the SG of NOD mice, the expression of soluble CD40:Fc did not lead to reduced overall inflammation and/or improved salivary gland function. These data indicate possible redundancy of the CD40 pathway in the SG and suggests that targeting CD40 alone may not be sufficient to alter the disease phenotype.
doi:10.1371/journal.pone.0051375
PMCID: PMC3530540  PMID: 23300544
13.  Real‐time quantitative PCR to detect changes in synovial gene expression in rheumatoid arthritis after corticosteroid treatment 
Annals of the Rheumatic Diseases  2006;66(4):545-547.
Synovial biomarkers are increasingly important in the development of novel therapeutic agents for the treatment of rheumatoid arthritis (RA). To identify biomarkers correlating with changes in clinical disease activity, real‐time quantitative PCR (Q‐PCR) was used to evaluate changes in synovial gene expression after treatment with corticosteroids. Patients with active RA received either oral prednisolone (n = 10, 60 mg daily for the first week and 40 mg daily for the second week) or placebo (n = 11) for 14 days. Real‐time Q‐PCR was used to quantify gene expression of tumour necrosis factor (TNF)α, IL1β, IL8 and matrix metalloproteinase (MMP) 1 in synovial tissue samples obtained through an arthroscopic procedure before and after treatment. mRNA levels were reported as relative expression units compared with a cell‐based standard. Statistical analysis was performed using an analysis of covariance model. Prednisolone markedly decreased IL8 and MMP1 expression compared with placebo, and the CIs excluded the likelihood of no effect. A trend towards reduction was seen in IL1β and TNFα mRNA expression in the prednisolone group, although CIs included the value for no effect. These data suggest that Q‐PCR can be used to measure synovial mRNA expression of mediators implicated in the pathogenesis of RA in small proof‐of‐concept trials.
doi:10.1136/ard.2006.059790
PMCID: PMC1856037  PMID: 16984938
14.  The Features of the Synovium in Early Rheumatoid Arthritis According to the 2010 ACR/EULAR Classification Criteria 
PLoS ONE  2012;7(5):e36668.
Objectives
It has been shown in early arthritis cohorts that the 2010 ACR/EULAR criteria for rheumatoid arthritis (RA) enable an earlier diagnosis, perhaps at the cost of a somewhat more heterogeneous patient population. We describe the features of synovial inflammation in RA patients classified according to these new criteria.
Methods
At baseline, synovial tissue biopsy samples were obtained from disease-modifying antirheumatic drug (DMARD)-naïve early RA patients (clinical signs and symptoms <1 year). Synovial tissue was analyzed for cell infiltration, vascularity, and expression of adhesion molecules. Stained sections were evaluated by digital image analysis. Patients were classified according to the two different sets of classification criteria, autoantibody status, and outcome.
Findings
Synovial tissue of 69 RA patients according to 2010 ACR/EULAR criteria was analyzed: 56 patients who fulfilled the criteria for RA at baseline and 13 who were initially diagnosed as undifferentiated arthritis but fulfilled criteria for RA upon follow up. The synovium at baseline was infiltrated by plasma cells, macrophages, and T cells as well as other cells, and findings were comparable to those when patients were selected based on the 1987 ACR criteria for RA. There was no clear cut difference in the characteristics of the synovium between RA patients initially diagnosed as undifferentiated arthritis and those who already fulfilled classification criteria at baseline.
Conclusion
The features of synovial inflammation are similar when the 2010 ACR/EULAR classification criteria are used compared to the 1987 ACR criteria.
doi:10.1371/journal.pone.0036668
PMCID: PMC3344938  PMID: 22574210
15.  Intimal lining layer macrophages but not synovial sublining macrophages display an IL-10 polarized-like phenotype in chronic synovitis 
Introduction
Synovial tissue macrophages play a key role in chronic inflammatory arthritis, but the contribution of different macrophage subsets in this process remains largely unknown. The main in vitro polarized macrophage subsets are classically (M1) and alternatively (M2) activated macrophages, the latter comprising interleukin (IL)-4 and IL-10 polarized cells. Here, we aimed to evaluate the polarization status of synovial macrophages in spondyloarthritis (SpA) and rheumatoid arthritis (RA).
Methods
Expression of polarization markers on synovial macrophages, peripheral blood monocytes, and in vitro polarized monocyte-derived macrophages from SpA versus RA patients was assessed by immunohistochemistry and flow cytometry, respectively. The polarization status of the intimal lining layer and the synovial sublining macrophages was assessed by double immunofluorescence staining.
Results
The expression of the IL-10 polarization marker cluster of differentiation 163 (CD163) was increased in SpA compared with RA intimal lining layer, but no differences were found in other M1 and M2 markers between the diseases. Furthermore, no significant phenotypic differences in monocytes and in vitro polarized monocyte-derived macrophages were seen between SpA, RA, and healthy controls, indicating that the differential CD163 expression does not reflect a preferential M2 polarization in SpA. More detailed analysis of intimal lining layer macrophages revealed a strong co-expression of the IL-10 polarization markers CD163 and cluster of differentiation 32 (CD32) but not any of the other markers in both SpA and RA. In contrast, synovial sublining macrophages had a more heterogeneous phenotype, with a majority of cells co-expressing M1 and M2 markers.
Conclusions
The intimal lining layer but not synovial sublining macrophages display an IL-10 polarized-like phenotype, with increased CD163 expression in SpA versus RA synovitis. These differences in the distribution of the polarized macrophage subset may contribute to the outcome of chronic synovitis.
doi:10.1186/ar3796
PMCID: PMC3446447  PMID: 22494514
16.  Statin therapy in lupus-mediated atherogenesis: two birds with one stone? 
Annals of the Rheumatic Diseases  2010;70(2):245-248.
The atherosclerotic process is accelerated in patients with systemic lupus erythematosus (SLE). In addition to a robust lipid-lowering effect, various immunomodulatory functions have been ascribed to statins. By virtue of the latter they may be able to reduce atherosclerotic vascular disease in SLE by inhibiting immune activation within the arterial wall and by attenuating lupus activity. The effects of statins on SLE as well as on lupus-mediated atherogenesis in vivo are discussed in this viewpoint.
doi:10.1136/ard.2010.133827
PMCID: PMC3306212  PMID: 21068103
17.  Sustained inhibition of progressive joint damage with rituximab plus methotrexate in early active rheumatoid arthritis: 2-year results from the randomised controlled trial IMAGE 
Annals of the Rheumatic Diseases  2011;71(3):351-357.
Background
In the IMAGE study, rituximab plus methotrexate (MTX) inhibited joint damage and improved clinical outcomes at 1 year in MTX-naïve patients with early active rheumatoid arthritis.
Objective
The aim of this study was to assess joint damage progression and clinical outcomes over 2 years.
Methods
Patients (n=755) were randomised to receive rituximab 2×500 mg+MTX, 2×1000 mg+MTX or placebo+MTX. The placebo-controlled period continued to week 104. Two-year end points were defined as secondary or exploratory and included change in total Genant-modified Sharp score (mTSS), total erosion score and joint space narrowing score from baseline to week 104. Clinical efficacy and physical function end points were also assessed.
Results
At 2 years, rituximab 2×1000 mg+MTX maintained inhibition of progressive joint damage versus MTX alone (mTSS change 0.41 vs 1.95; p<0.0001 (79% inhibition)), and a higher proportion of patients receiving rituximab 2×1000 mg+MTX had no radiographic progression over 2 years compared with those receiving MTX alone (57% vs 37%; p<0.0001). Contrary to 1-year results, exploratory analysis of rituximab 2×500 mg+MTX at 2 years showed that progressive joint damage was slowed by ∼61% versus placebo+MTX (mTSS, exploratory p=0.0041). Improvements in clinical signs and symptoms and physical function seen after 1 year in rituximab-treated patients versus those receiving placebo were maintained at year 2. Safety profiles were similar between groups.
Conclusions
Treatment with rituximab 2×1000 mg+MTX was associated with sustained improvements in radiographic, clinical and functional outcomes over 2 years.
Clinical trials.gov identifier NCT00299104.
doi:10.1136/annrheumdis-2011-200170
PMCID: PMC3277723  PMID: 22012969
18.  Integration of Sequence Data from a Consanguineous Family with Genetic Data from an Outbred Population Identifies PLB1 as a Candidate Rheumatoid Arthritis Risk Gene 
PLoS ONE  2014;9(2):e87645.
Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2×10−6). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted.
doi:10.1371/journal.pone.0087645
PMCID: PMC3919745  PMID: 24520335
19.  Signal Transduction Pathways in Chronic Inflammatory Autoimmune Disease: Small GTPases 
Ras superfamily small GTPases represent a wide and diverse class of intracellular signaling proteins that are highly conserved during evolution. These enzymes serve as key checkpoints in coupling antigen receptor, growth factor, cytokine and chemokine stimulation to cellular responses. Once activated, via their ability to regulate multiple downstream signaling pathways, small GTPases amplify and diversify signaling cascades which regulate cellular proliferation, survival, cytokine expression, trafficking and retention. Small GTPases, particularly members of the Ras, Rap, and Rho family, critically coordinate the function and interplay of immune and stromal cells during inflammatory respones, and increasing evidence indicates that alterations in small GTPase signaling contribute to the pathological behavior of these cell populations in human chronic inflammatory diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Here, we review how Ras, Rap, and Rho family GTPases contribute to the biology of cell populations relevant to human chronic inflammatory disease, highlight recent advances in understanding how alterations in these pathways contribute to pathology in RA and SLE, and discuss new therapeutic strategies that may allow specific targeting of small GTPases in the clinic.
doi:10.2174/1874312901206010259
PMCID: PMC3460313  PMID: 23028410
GTPases; systemic lupus erythematosus; matrix metalloproteinases; farnesyltransferase inhibitors.
21.  Advancements in adeno-associated viral gene therapy approaches: exploring a new horizon 
Gene therapy is a promising new therapeutic strategy that has been explored in a wide variety of diseases, ranging from cancer to hemophilia, and ocular disorders to autoimmune diseases, among others. Proof of concept of gene transfer approaches has been shown in over 100 studies of animal models of disease, although only a few are under development for clinical application. The US Food and Drug Administration and the European Medicines Agency have not approved any viral human gene therapy products for sale so far, but the amount of gene-related research and development occurring in the United States and Europe continues to grow at a fast rate. This review summarizes the current status of developments in the field of viral gene therapy using adeno-associated virus as a vector, with a special focus on arthritis. For rheumatoid arthritis, and to a lesser extent for other immune-related inflammatory disorders, several cell and gene transfer approaches have been investigated at the preclinical level and a few have been implemented in clinical trials. Finally, both the potential and the hurdles that are faced during development of a viral gene therapy through to its clinical application are discussed.
doi:10.3410/M3-17
PMCID: PMC3169911  PMID: 21941595
22.  Restoring the Balance of the Autonomic Nervous System as an Innovative Approach to the Treatment of Rheumatoid Arthritis 
Molecular Medicine  2011;17(9-10):937-948.
The immunomodulatory effect of the autonomic nervous system has raised considerable interest over the last decades. Studying the influence on the immune system and the role in inflammation of the sympathetic as well as the parasympathetic nervous system not only will increase our understanding of the mechanism of disease, but also could lead to the identification of potential new therapeutic targets for chronic immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA). An imbalanced autonomic nervous system, with a reduced parasympathetic and increased sympathetic tone, has been a consistent finding in RA patients. Studies in animal models of arthritis have shown that influencing the sympathetic (via α- and β-adrenergic receptors) and the parasympathetic (via the nicotinic acetylcholine receptor α7nAChR or by electrically stimulating the vagus nerve) nervous system can have a beneficial effect on inflammation markers and arthritis. The immunosuppressive effect of the parasympathetic nervous system appears less ambiguous than the immunomodulatory effect of the sympathetic nervous system, where activation can lead to increased or decreased inflammation depending on timing, doses and kind of adrenergic agent used. In this review we will discuss the current knowledge of the role of both the sympathetic (SNS) and parasympathetic nervous system (PNS) in inflammation with a special focus on the role in RA. In addition, potential antirheumatic strategies that could be developed by targeting these autonomic pathways are discussed.
doi:10.2119/molmed.2011.00065
PMCID: PMC3188868  PMID: 21607292
23.  Altered Expression of MicroRNA-203 in Rheumatoid Arthritis Synovial Fibroblasts and Its Role in Fibroblast Activation 
Arthritis and rheumatism  2011;63(2):373-381.
Objective
MicroRNA (miRNA) are recognized as important regulators of a variety of fundamental biologic processes. Previously, we described increased expression of miR-155 and miR-146a in rheumatoid arthritis (RA) and showed a repressive effect of miR-155 on matrix metalloproteinase (MMP) expression in RA synovial fibroblasts (RASFs). The present study was undertaken to examine alterations in expression of miR-203 in RASFs and analyze its role in fibroblast activation.
Methods
Differentially expressed miRNA in RASFs versus osteoarthritis synovial fibroblasts (OASFs) were identified by real-time polymerase chain reaction (PCR)–based screening of 260 individual miRNA. Transfection of miR-203 precursor was used to analyze the function of miR-203 in RASFs. Levels of interleukin-6 (IL-6) and MMPs were measured by real-time PCR and enzyme-linked immunosorbent assay. RASFs were stimulated with IL-1β, tumor necrosis factor α (TNFα), lipopolysaccharide (LPS), and 5-azacytidine (5-azaC). Activity of IκB kinase 2 was inhibited with SC-514.
Results
Expression of miR-203 was higher in RASFs than in OASFs or fibroblasts from healthy donors. Levels of miR-203 did not change upon stimulation with IL-1β, TNFα, or LPS; however, DNA demethylation with 5-azaC increased the expression of miR-203. Enforced expression of miR-203 led to significantly increased levels of MMP-1 and IL-6. Induction of IL-6 by miR-203 overexpression was inhibited by blocking of the NF-κB pathway. Basal expression levels of IL-6 correlated with basal expression levels of miR-203.
Conclusion
The current results demonstrate methylation-dependent regulation of miR-203 expression in RASFs. Importantly, they also show that elevated levels of miR-203 lead to increased secretion of MMP-1 and IL-6 via the NF-κB pathway and thereby contribute to the activated phenotype of synovial fibroblasts in RA.
doi:10.1002/art.30115
PMCID: PMC3116142  PMID: 21279994
24.  Advances in rheumatology: new targeted therapeutics 
Arthritis Research & Therapy  2011;13(Suppl 1):S5.
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.
doi:10.1186/1478-6354-13-S1-S5
PMCID: PMC3123966  PMID: 21624184
25.  Effect of Soluble ICAM-1 on a Sjögren's Syndrome-like Phenotype in NOD Mice Is Disease Stage Dependent 
PLoS ONE  2011;6(5):e19962.
Introduction
Intercellular adhesion molecule-1 (ICAM-1) is involved in migration and co-stimulation of T and B cells. Membrane bound ICAM-1 is over expressed in the salivary glands (SG) of Sjögren's syndrome (SS) patients and has therefore been proposed as a potential therapeutic target. To test the utility of ICAM-1 as a therapeutic target, we used local gene therapy in Non Obese Diabetic (NOD) mice to express soluble (s)ICAM-1 to compete with membrane bound ICAM-1 for binding with its receptor. Therapy was given prior to and just after the influx of immune cells into the SG.
Methods
A recombinant serotype 2 adeno associated virus (rAAV2) encoding ICAM-1/Fc was constructed and its efficacy tested in the female NOD mice after retrograde instillation in SG at eight (early treatment) and ten (late treatment) weeks of age. SG inflammation was evaluated by focus score and immunohistochemical quantification of infiltrating cell types. Serum and SG tissue were analyzed for immunoglobulins (Ig).
Results
Early treatment with ICAM-1/Fc resulted in decreased average number of inflammatory foci without changes in T and B cell composition. In contrast, late treated mice did not show any change in focus scores, but immunohistochemical staining showed an increase in the overall number of CD4+ and CD8+ T cells. Moreover, early treated mice showed decreased IgM within the SGs, whereas late treated mice had increased IgM levels, and on average higher IgG and IgA.
Conclusions
Blocking the ICAM-1/LFA-1 interaction with sICAM-1/Fc may result in worsening of a SS like phenotype when infiltrates have already formed within the SG. As a treatment for human SS, caution should be taken targeting the ICAM-1 axis since most patients are diagnosed when inflammation is clearly present within the SG.
doi:10.1371/journal.pone.0019962
PMCID: PMC3093404  PMID: 21589878

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