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1.  Persistence of interleukin 7 activity and levels on tumour necrosis factor α blockade in patients with rheumatoid arthritis 
Annals of the Rheumatic Diseases  2006;66(5):664-669.
Objectives
To identify the mechanism of interleukin (IL)7‐stimulated tumour necrosis factor α (TNFα) production and to determine the relationship between intra‐articular IL7 and TNFα expression levels in patients with rheumatoid arthritis (RA). In addition, the effect of TNFα blockade on IL7 activity and on IL7 levels was studied.
Methods
The effect of IL7 on isolated CD4 T cells and CD14 monocytes/macrophages was studied. IL7 and TNFα levels were measured in the synovial fluid of patients with RA. In RA synovial tissue, IL7 and TNFα expression was assessed in addition to IL1β, numbers of inflammatory cells and adhesion molecule expression. The extent to which TNFα blockade could prevent IL7‐induced lymphocyte responses was studied in vitro. In addition, regulation of serum IL7 levels on anti‐TNFα therapy (adalimumab) was studied.
Results
IL7 induced cell contact‐dependent TNFα production by cocultures of T cells and monocytes, but not by T cells and monocytes cultured separately. IL7 and TNFα levels in RA synovial fluid and synovial tissue significantly correlated. IL7‐stimulated lymphocyte responses were not inhibited by TNFα blockade. Circulating IL7 levels were significantly reduced in patients who successfully responded to anti‐TNFα treatment. However, IL7 levels persisted in non‐responders.
Conclusion
The present data suggest that IL7 is an important inducer of T cell‐dependent TNFα production in RA joints. This may contribute to the correlation of intra‐articular IL7 and TNFα in these joints. Furthermore, the persistence of IL7‐induced inflammatory activity on TNFα blockade in vitro and persistence of IL7 levels and disease activity in anti‐TNFα non‐responders suggest that IL7 might additionally promote TNFα‐independent inflammation.
doi:10.1136/ard.2006.062547
PMCID: PMC1954618  PMID: 17185327
3.  Patient benefit–risk in arthritis—a rheumatologist’s perspective 
Rheumatology (Oxford, England)  2010;49(Suppl 2):ii11-ii17.
There is a range of pharmacological options available to the rheumatologist for treating arthritis. Non-selective NSAIDs or Cox-2 selective inhibitors are widely prescribed to reduce inflammation and alleviate pain; however, they must be used with caution in individuals with an increased cardiovascular, renal or gastrointestinal (GI) risk. The potential cardiovascular risks of Cox-2 selective inhibitors came to light over a decade ago. The conflicting nature of the study data reflects some context dependency, but the evidence shows a varying degree of cardiovascular risk with both Cox-2 selective inhibitors and non-selective NSAIDs. This risk appears to be dose dependent, which may have important ramifications for arthritis patients who require long-term treatment with high doses of anti-inflammatory drugs. The renal effects of non-selective NSAIDs have been well characterized. An increased risk of adverse renal events was found with rofecoxib but not celecoxib, suggesting that this is not a class effect of Cox-2 selective inhibitors. Upper GI effects of non-selective NSAID treatment, ranging from abdominal pain to ulceration and bleeding are extensively documented. Concomitant prescription of a proton pump inhibitor can help in the upper GI tract, but probably not in the lower. Evidence suggests that Cox-2 selective inhibitors are better tolerated in the entire GI tract. More evidence is required, and a composite end-point is being evaluated. Appropriate treatment strategies are needed depending on the level of upper and lower GI risk. Rheumatologists must be vigilant in assessing benefit–risk when prescribing a Cox-2 selective inhibitor or non-selective NSAID and should choose appropriate agents for each individual patient.
doi:10.1093/rheumatology/keq057
PMCID: PMC2857791  PMID: 20407136
Gastrointestinal bleeding; Cox-2 selective inhibitors; NSAID; Celecoxib; Diclofenac; Ibuprofen; Cardiovascular risk; Renal risk; Ulcers; Proton pump inhibitors
4.  Modulation of monocyte/macrophage function by human CD4+CD25+ regulatory T cells 
Human immunology  2005;66(3):222-230.
SUMMARY
The suppressive effects of CD4+CD25+ regulatory T cells (Tregs) on T cells have been well documented. Here we investigated whether human CD4+CD25+ Tregs can inhibit the pro-inflammatory properties of monocytes/macrophages. Monocytes and T cells were isolated from peripheral blood of healthy volunteers by magnetic cell separation, and co-cultured for 40 hours. Monocytes were analyzed directly for cytokine production and phenotypic changes, or re-purified and used in T cell stimulation and LPS challenge assays. Co-culture with CD4+CD25+ Tregs induced minimal cytokine production in monocytes, whereas co-culture with CD4+CD25− T cells resulted in large amounts of pro-inflammatory (TNF-α, IFN-γ IL-6) and regulatory (IL-10) cytokines. Importantly, when these CD4+CD25+ Treg-treated monocytes were re-purified after co-culture and challenged with LPS, they were severely inhibited in their capacity to produce TNF-α and IL-6 compared to control-treated monocytes. In addition, monocytes that were pre-cultured with CD4+CD25+ Tregs displayed limited up-regulation of HLA class II, CD40 and CD80, and down-regulation of CD86 compared to control-treated monocytes. This altered phenotype had functional consequences, as shown by the reduction in T cell-stimulatory capacity of Treg-treated monocytes. Together these data demonstrate that CD4+CD25+ Tregs can exert direct suppressive effects on monocytes/macrophages, thereby affecting subsequent innate and adaptive immune responses.
doi:10.1016/j.humimm.2004.12.006
PMCID: PMC3904343  PMID: 15784460
Suppression; antigen-presenting cell; rheumatoid arthritis
5.  Performance of a multi-biomarker score measuring rheumatoid arthritis disease activity in the CAMERA tight control study 
Annals of the Rheumatic Diseases  2012;71(10):1692-1697.
Objectives
To evaluate the performance of individual biomarkers and a multi-biomarker disease activity (MBDA) score in the early rheumatoid arthritis (RA) patient population from the computer assisted management in early rheumatoid arthritis (CAMERA) study.
Methods
Twenty biomarkers were measured in the CAMERA cohort, in which patients were treated with either intensive or conventional methotrexate-based treatment strategies. The MBDA score was calculated using the concentrations of 12 biomarkers (SAA, IL-6, TNF-RI, VEGF-A, MMP-1, YKL-40, MMP-3, EGF, VCAM-1, leptin, resistin and CRP) according to a previously trained algorithm. The performance of the scores was evaluated relative to clinical disease activity assessments. Change in MBDA score over time was assessed by paired Wilcoxon rank sum test. Logistic regression was used to evaluate the ability of disease activity measures to predict radiographic progression.
Results
The MBDA score had a significant correlation with the disease activity score based on 28 joints-C reactive protein (DAS28-CRP) (r=0.72; p<0.001) and an area under the receiver operating characteristic curve for distinguishing remission/low from moderate/high disease activity of 0.86 (p<0.001) using a DAS28-CRP cut-off of 2.7. In multivariate analysis the MBDA score, but not CRP, was an independent predictor of disease activity measures. Additionally, mean (SD) MBDA score decreased from 53 (18) at baseline to 39 (16) at 6 months in response to study therapy (p<0.0001). Neither MBDA score nor clinical variables were predictive of radiographic progression.
Conclusions
This multi-biomarker test performed well in the assessment of disease activity in RA patients in the CAMERA study. Upon further validation, this test could be used to complement currently available disease activity measures and improve patient care and outcomes.
doi:10.1136/annrheumdis-2011-200963
PMCID: PMC3439649  PMID: 22596166
6.  Tissue structure modification in knee osteoarthritis by use of joint distraction: an open 1-year pilot study 
Annals of the Rheumatic Diseases  2011;70(8):1441-1446.
Background
Modification of joint tissue damage is challenging in late-stage osteoarthritis (OA). Few options are available for treating end-stage knee OA other than joint replacement.
Objectives
To examine whether joint distraction can effectively modify knee joint tissue damage and has the potential to delay prosthesis surgery.
Methods
20 patients (<60 years) with tibiofemoral OA were treated surgically using joint distraction. Distraction (∼5 mm) was applied for 2 months using an external fixation frame. Tissue structure modification at 1 year of follow-up was evaluated radiographically (joint space width (JSW)), by MRI (segmentation of cartilage morphology) and by biochemical markers of collagen type II turnover, with operators blinded to time points. Clinical improvement was evaluated by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Visual Analogue Scale (VAS) pain score.
Results
Radiography demonstrated an increase in mean and minimum JSW (2.7 to 3.6 mm and 1.0 to 1.9 mm; p<0.05 and <0.01). MRI revealed an increase in cartilage thickness (2.4 to 3.0 mm; p<0.001) and a decrease of denuded bone areas (22% to 5%; p<0.001). Collagen type II levels showed a trend towards increased synthesis (+103%; p<0.06) and decreased breakdown (−11%; p<0.08). The WOMAC index increased from 45 to 77 points, and VAS pain decreased from 73 to 31 mm (both p<0.001).
Conclusions
Joint distraction can induce tissue structure modification in knee OA and could result in clinical benefit. No current treatment is able to induce such changes. Larger, longer and randomised studies on joint distraction are warranted.
doi:10.1136/ard.2010.142364
PMCID: PMC3128325  PMID: 21565898
7.  Optimal use of methotrexate: the advantages of tight control 
Annals of the Rheumatic Diseases  2007;66(11):1409-1410.
The CAMERA study shows that using methotrexate in a tight control setting might lead to considerable improvement in disease activity in early rheumatoid arthritisSee linked article p 1443
doi:10.1136/ard.2007.076463
PMCID: PMC2111621  PMID: 17934080
8.  Adalimumab alone and in combination with disease‐modifying antirheumatic drugs for the treatment of rheumatoid arthritis in clinical practice: the Research in Active Rheumatoid Arthritis (ReAct) trial 
Annals of the Rheumatic Diseases  2007;66(6):732-739.
Objective
To evaluate the safety and effectiveness of adalimumab alone or in combination with standard disease‐modifying antirheumatic drugs (DMARDs) for the treatment of rheumatoid arthritis (RA).
Methods
Patients with active RA despite treatment with DMARDs or prior treatment with a tumour necrosis factor antagonist participated in a multicentre, open‐label clinical study of adalimumab 40 mg every other week for 12 weeks with an optional extension phase. Patients were allowed to continue with pre‐existing traditional DMARDs. Long‐term safety results are reported for all patients (4210 patient‐years (PYs) of adalimumab exposure). The observed effectiveness results at week 12 are reported using American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria.
Results
Among the 6610 treated patients, adalimumab was generally well tolerated. Serious infections occurred in 3.1% of patients (5.5/100 PYs, including active tuberculosis, 0.5/100 PYs). Demyelinating disease (0.06%) and systemic lupus erythematosus (0.03%) were rare serious adverse events. The standardised incidence ratio of malignancy was 0.71 (95% CI 0.49 to 1.01). The standardised mortality ratio was 1.07 (95% CI 0.75 to 1.49). At week 12, 69% of patients achieved an ACR20 response, 83% a moderate, and 33% a good EULAR response. Adalimumab was effective in combination with a variety of DMARDs. The addition of adalimumab to antimalarials was comparably effective to the combination of adalimumab and methotrexate.
Conclusions
Considering the limitations of an open‐label study, adalimumab alone or in combination with standard DMARDs appeared to be well tolerated and effective in 6610 difficult‐to‐treat patients with active RA treated in clinical practice.
doi:10.1136/ard.2006.066761
PMCID: PMC1954645  PMID: 17329305
adalimumab; rheumatoid arthritis; tumour necrosis factor; monoclonal antibody; antirheumatic agents
9.  EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs 
Annals of the Rheumatic Diseases  2010;69(6):964-975.
Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available. In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described. The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues. The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process. Levels of evidence, strength of recommendations and levels of agreement were derived. Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-à-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed. Cost effectiveness of the treatments was additionally examined. These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion.
doi:10.1136/ard.2009.126532
PMCID: PMC2935329  PMID: 20444750
10.  Evidence for treating rheumatoid arthritis to target: results of a systematic literature search 
Annals of the Rheumatic Diseases  2010;69(4):638-643.
Objectives
To summarise existing evidence on a target oriented approach for rheumatoid arthritis (RA) treatment.
Methods
We conducted a systematic literature search including all clinical trials testing clinical, functional, or structural values of a targeted treatment approach. Our search covered Medline, Embase and Cochrane databases until December 2008 and also conference abstracts (2007, 2008).
Results
The primary search yielded 5881 citations; after the selection process, 76 papers underwent detailed review. Of these, only seven strategic clinical trials were extracted: four studies randomised patients to routine or targeted treatment, two compared two different randomised targets and one compared targeted treatment to a historical control group. Five trials dealt with early RA patients. All identified studies showed significantly better clinical outcomes of targeted approaches than routine approaches. Disability was reported in two studies with no difference between groups. Four studies compared radiographic outcomes, two showing significant benefit of the targeted approach.
Conclusion
Only few studies employed randomised controlled settings to test the value of treatment to a specific target. However, they provided unanimous evidence for benefits of targeted approaches. Nevertheless, more data on radiographic and functional outcomes and on patients with established RA are needed.
doi:10.1136/ard.2009.123976
PMCID: PMC3015093  PMID: 20237123
11.  Treating rheumatoid arthritis to target: recommendations of an international task force 
Annals of the Rheumatic Diseases  2010;69(4):631-637.
Background
Aiming at therapeutic targets has reduced the risk of organ failure in many diseases such as diabetes or hypertension. Such targets have not been defined for rheumatoid arthritis (RA).
Objective
To develop recommendations for achieving optimal therapeutic outcomes in RA.
Methods
A task force of rheumatologists and a patient developed a set of recommendations on the basis of evidence derived from a systematic literature review and expert opinion; these were subsequently discussed, amended and voted upon by >60 experts from various regions of the world in a Delphi-like procedure. Levels of evidence, strength of recommendations and levels of agreement were derived.
Results
The treat-to-target activity resulted in 10 recommendations. The treatment aim was defined as remission with low disease activity being an alternative goal in patients with long-standing disease. Regular follow-up (every 1–3 months during active disease) with appropriate therapeutic adaptation to reach the desired state within 3 to a maximum of 6 months was recommended. Follow-up examinations ought to employ composite measures of disease activity which include joint counts. Additional items provide further details for particular aspects of the disease. Levels of agreement were very high for many of these recommendations (≥9/10).
Conclusion
The 10 recommendations are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA based on evidence and expert opinion.
doi:10.1136/ard.2009.123919
PMCID: PMC3015099  PMID: 20215140
12.  The cost effectiveness of behavioural graded activity in patients with osteoarthritis of hip and/or knee 
Annals of the Rheumatic Diseases  2006;66(2):215-221.
Objective
To evaluate whether exercise treatment based on behavioural graded activity comprising booster sessions is a cost‐effective treatment for patients with osteoarthritis of the hip and/or knee compared with usual care.
Methods
An economic evaluation from a societal perspective was carried out alongside a randomised trial involving 200 patients with osteoarthritis of the hip and/or knee. Outcome measures were pain, physical functioning, self‐perceived change and quality of life, assessed at baseline, 13, 39 and 65 weeks. Costs were measured using cost diaries for the entire follow‐up period of 65 weeks. Cost and effect differences were estimated using multilevel analysis. Uncertainty around the cost‐effectiveness ratios was estimated by bootstrapping and graphically represented on cost‐effectiveness planes.
Results
97 patients received behavioural graded activity, and 103 patients received usual care. At 65 weeks, no differences were found between the two groups in improvement with respect to baseline on any of the outcome measures. The mean (95% confidence interval) difference in total costs between the groups was −€773 (−€2360 to €772)—that is, behavioural graded activity resulted in less cost but this difference was non‐significant. As effect differences were small, a large incremental cost‐effectiveness ratio of €51 385 per quality adjusted life year was found for graded activity versus usual care.
Conclusions
This study provides no evidence that behavioural graded activity is either more effective or less costly than usual care. Yielding similar results to usual care, behavioural graded activity seems an acceptable method for treating patients with osteoarthritis of the hip and/or knee.
doi:10.1136/ard.2006.054478
PMCID: PMC1798485  PMID: 16880195
13.  EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update 
Annals of the Rheumatic Diseases  2013;73(3):492-509.
In this article, the 2010 European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs (sDMARDs and bDMARDs, respectively) have been updated. The 2013 update has been developed by an international task force, which based its decisions mostly on evidence from three systematic literature reviews (one each on sDMARDs, including glucocorticoids, bDMARDs and safety aspects of DMARD therapy); treatment strategies were also covered by the searches. The evidence presented was discussed and summarised by the experts in the course of a consensus finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) were determined. Fourteen recommendations were developed (instead of 15 in 2010). Some of the 2010 recommendations were deleted, and others were amended or split. The recommendations cover general aspects, such as attainment of remission or low disease activity using a treat-to-target approach, and the need for shared decision-making between rheumatologists and patients. The more specific items relate to starting DMARD therapy using a conventional sDMARD (csDMARD) strategy in combination with glucocorticoids, followed by the addition of a bDMARD or another csDMARD strategy (after stratification by presence or absence of adverse risk factors) if the treatment target is not reached within 6 months (or improvement not seen at 3 months). Tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, biosimilars), abatacept, tocilizumab and, under certain circumstances, rituximab are essentially considered to have similar efficacy and safety. If the first bDMARD strategy fails, any other bDMARD may be used. The recommendations also address tofacitinib as a targeted sDMARD (tsDMARD), which is recommended, where licensed, after use of at least one bDMARD. Biosimilars are also addressed. These recommendations are intended to inform rheumatologists, patients, national rheumatology societies and other stakeholders about EULAR's most recent consensus on the management of RA with sDMARDs, glucocorticoids and bDMARDs. They are based on evidence and expert opinion and intended to improve outcome in patients with RA.
doi:10.1136/annrheumdis-2013-204573
PMCID: PMC3933074  PMID: 24161836
Rheumatoid Arthritis; DMARDs (synthetic); DMARDs (biologic); Treatment; Early Rheumatoid Arthritis
14.  Multinational evidence-based recommendations for pain management by pharmacotherapy in inflammatory arthritis: integrating systematic literature research and expert opinion of a broad panel of rheumatologists in the 3e Initiative 
Rheumatology (Oxford, England)  2012;51(8):1416-1425.
Objective. To develop evidence-based recommendations for pain management by pharmacotherapy in patients with inflammatory arthritis (IA).
Methods. A total of 453 rheumatologists from 17 countries participated in the 2010 3e (Evidence, Expertise, Exchange) Initiative. Using a formal voting process, 89 rheumatologists representing all 17 countries selected 10 clinical questions regarding the use of pain medications in IA. Bibliographic fellows undertook a systematic literature review for each question, using MEDLINE, EMBASE, Cochrane CENTRAL and 2008–09 European League Against Rheumatism (EULAR)/ACR abstracts. Relevant studies were retrieved for data extraction and quality assessment. Rheumatologists from each country used this evidence to develop a set of national recommendations. Multinational recommendations were then formulated and assessed for agreement and the potential impact on clinical practice.
Results. A total of 49 242 references were identified, from which 167 studies were included in the systematic reviews. One clinical question regarding different comorbidities was divided into two separate reviews, resulting in 11 recommendations in total. Oxford levels of evidence were applied to each recommendation. The recommendations related to the efficacy and safety of various analgesic medications, pain measurement scales and pain management in the pre-conception period, pregnancy and lactation. Finally, an algorithm for the pharmacological management of pain in IA was developed. Twenty per cent of rheumatologists reported that the algorithm would change their practice, and 75% felt the algorithm was in accordance with their current practice.
Conclusions. Eleven evidence-based recommendations on the management of pain by pharmacotherapy in IA were developed. They are supported by a large panel of rheumatologists from 17 countries, thus enhancing their utility in clinical practice.
doi:10.1093/rheumatology/kes032
PMCID: PMC3397467  PMID: 22447886
arthritis; evidence-based medicine; analgesics

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