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1.  CD4+CD25-Foxp3+ T cells: a marker for lupus nephritis? 
Arthritis Research & Therapy  2014;16(2):R104.
Introduction
Systemic lupus erythematosus (SLE) is a heterogenous autoimmune disease, which can affect different organs. Increased proportions of CD4+CD25-Foxp3+ T cells have been described in SLE patients. The exact role of this cell population in SLE patients still remains unclear. We therefore analyzed this T cell subset in a large cohort of SLE patients with different organ manifestations.
Methods
Phenotypic analyses, proportions and absolute cell numbers of CD4+CD25-Foxp3+ T cells were determined by flow cytometry (FACS) in healthy controls (HC) (n = 36) and SLE patients (n = 61) with different organ manifestations. CD4+CD25-Foxp3+ T cells were correlated with clinical data, the immunosuppressive therapy and different disease activity indices. In patients with active glomerulonephritis, CD4+CD25-Foxp3+ T cells were analyzed in urine sediment samples. Time course analyses of CD4+CD25-Foxp3+ T cells were performed in patients with active disease activity before and after treatment with cyclophosphamide and prednisone.
Results
CD4+CD25-Foxp3+ T cells were significantly increased in active SLE patients and the majority expressed Helios. Detailed analysis of this patient cohort revealed increased proportions of CD4+CD25-Foxp3+ T cells in SLE patients with renal involvement. CD4+CD25-Foxp3+ T cells were also detected in urine sediment samples of patients with active glomerulonephritis and correlated with the extent of proteinuria.
Conclusion
CD4+CD25-Foxp3+ T cells resemble regulatory rather than activated T cells. Comparative analysis of CD4+CD25-Foxp3+ T cells in SLE patients revealed a significant association of this newly described cell population with active nephritis. Therefore CD4+CD25-Foxp3+ T cells might serve as an important tool to recognize and monitor SLE patients with renal involvement.
doi:10.1186/ar4553
PMCID: PMC4060257  PMID: 24774748
2.  Development of a new occupational balance-questionnaire: incorporating the perspectives of patients and healthy people in the design of a self-reported occupational balance outcome instrument 
Background
Self-reported outcome instruments in health research have become increasingly important over the last decades. Occupational therapy interventions often focus on occupational balance. However, instruments to measure occupational balance are scarce. The aim of the study was therefore to develop a generic self-reported outcome instrument to assess occupational balance based on the experiences of patients and healthy people including an examination of its psychometric properties.
Methods
We conducted a qualitative analysis of the life stories of 90 people with and without chronic autoimmune diseases to identify components of occupational balance. Based on these components, the Occupational Balance-Questionnaire (OB-Quest) was developed. Construct validity and internal consistency of the OB-Quest were examined in quantitative data. We used Rasch analyses to determine overall fit of the items to the Rasch model, person separation index and potential differential item functioning. Dimensionality testing was conducted by the use of t-tests and Cronbach’s alpha.
Results
The following components emerged from the qualitative analyses: challenging and relaxing activities, activities with acknowledgement by the individual and by the sociocultural context, impact of health condition on activities, involvement in stressful activities and fewer stressing activities, rest and sleep, variety of activities, adaptation of activities according to changed living conditions and activities intended to care for oneself and for others. Based on these, the seven items of the questionnaire (OB-Quest) were developed. 251 people (132 with rheumatoid arthritis, 43 with systematic lupus erythematous and 76 healthy) filled in the OB-Quest. Dimensionality testing indicated multidimensionality of the questionnaire (t = 0.58, and 1.66 after item reduction, non-significant). The item on the component rest and sleep showed differential item functioning (health condition and age). Person separation index was 0.51. Cronbach’s alpha changed from 0.38 to 0.57 after deleting two items.
Conclusions
This questionnaire includes new items addressing components of occupational balance meaningful to patients and healthy people which have not been measured so far. The reduction of two items of the OB-Quest showed improved internal consistency. The multidimensionality of the questionnaire indicates the need for a summary of several components into subscales.
doi:10.1186/1477-7525-12-45
PMCID: PMC4005851  PMID: 24708642
Qualitative research; Rasch analysis; Occupational science; Patient perspective
3.  Efficacy of conventional synthetic disease-modifying antirheumatic drugs, glucocorticoids and tofacitinib: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis 
Annals of the Rheumatic Diseases  2014;73(3):510-515.
Objectives
To update a previous systematic review assessing the efficacy of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in rheumatoid arthritis (RA).
Methods
Two systematic reviews of the literature using PubMed, Embase and the Cochrane library were performed from 2009 until January 2013 to assess the efficacy of csDMARDs (as monotherapy or combination therapy) in adults with RA, and the efficacy of glucocorticoids in early RA. A third systematic review was performed until March 2013 to assess the efficacy of tofacitinib by meta-analysis.
Results
For glucocorticoids, of 222 hits, five publications relating to four new trials were analysed for efficacy, confirming that initial treatment of RA with low-dose prednisone plus methotrexate (MTX) results in better clinical and structural outcomes at 1 and 2 years than treatment with MTX alone. For csDMARDs, of 498 studies, only two new studies were randomised controlled trials comparing MTX monotherapy with MTX in combination with another csDMARD without differences in glucocorticoid usage. Using tight control principles, clinical outcomes were no better with immediate triple therapy than with ‘step-up’ therapy. For tofacitinib, the pooled analysis of 10 trials showed that tofacitinib was more efficacious on signs and symptoms, disability and appeared to be more efficacious on structural damage than control treatment with placebo (OR (95% CI)—American College of Rheumatology 20% (ACR20) response: 2.44 (1.97 to 3.02)) or treatment with MTX (ACR20 response: 2.38 (1.66 to 3.43)).
Conclusions
Addition of low-dose glucocorticoids to csDMARD therapy produces benefits in early RA. Under tight control conditions, combination therapy with csDMARDs is no better than MTX monotherapy. Tofacitinib is a new DMARD with proven efficacy.
doi:10.1136/annrheumdis-2013-204588
PMCID: PMC3932966  PMID: 24395555
Rheumatoid Arthritis; Treatment; Corticosteroids; DMARDs (synthetic)
4.  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
5.  Remission in rheumatoid arthritis: benefit over low disease activity in patient-reported outcomes and costs 
Introduction
Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes a considerable burden for the patient and society. It is not clear yet whether aiming for remission (REM) is worthwhile, especially when compared with low disease activity (LDA).
Methods
In 356 consecutive RA patients, we obtained data on physical function (health assessment questionnaire (HAQ)), health-related quality of life (HRQoL: Short Form 36 (SF36), Short Form 6 dimensions (SF-6D), Euro QoL 5D (EQ-5D)), work productivity (work productivity and activity impairment questionnaire (WPAI)), as well as estimation of direct and indirect costs. Cross-sectionally, data were compared in patients within different levels of disease activity according to the simplified disease activity index (SDAI; remission (REM ≤3.3); n = 87; low disease activity (LDA: 3.3 < SDAI ≤11); n = 103; moderate to high disease activity (MDA/HDA) >11 n = 119) by using analyses of variance (ANOVA). Longitudinal investigations assessed patients who changed from LDA to REM and vice versa.
Results
We found differences in patients achieving REM compared with LDA for HAQ (0.39 ± 0.58 versus 0.72 ± 68), WPAI (percentage impairment while working 11.8% ± 18.7% versus 26.8% ± 23.9%; percentage of overall activity impairment, 10.8% ± 14.1% versus 29.0% ± 23.6%)), EQ-5D (0.89 ± 0.12 versus 0.78 ± 0.6) and SF-36 (physical component score (PCS): 46.0 ± 8.6 versus 38.3 ± 10.5; mental component score (MCS): 49.9 ± 11.1 versus 47.9 ± 12.3) (P < 0.01 for all, except for SF36 MCS). Regarding costs, we found significant differences of direct and indirect costs (P < 0.05) within different levels of disease activity, with higher costs in patients with higher states of disease activity. Longitudinal evaluations confirmed the main analyses.
Conclusion
Patients with REM show better function, HRQoL, and productivity, even when compared with another good state, such as LDA. Also from a cost perspective, REM appears superior to all other states.
doi:10.1186/ar4491
PMCID: PMC3979137  PMID: 24555808
6.  Health determining concepts important to people with Crohn's disease and their coverage by patient-reported outcomes of health and wellbeing☆☆☆ 
Journal of Crohn's & Colitis  2014;8(1):45-55.
Background and aims
Busy clinical settings often restrict the possibility to focus on concepts that determine health in a positive way, commonly assessed by using patient-reported outcomes (PROs). We aimed to explore which determinants of health (DHs) are important to people with Crohn's disease (CD), to understand possible gender differences and to analyze whether these DHs are covered by PROs used in CD.
Methods
Two systematic literature reviews were done to identify relevant DHs and clinically relevant PROs. We conducted a qualitative narrative biographical study and mapped the patients' experiences to concepts that determine health in a positive way. Experiences, DHs and the items of the PROs were compared by the WHO International Classification of Functioning, Disability and Health (ICF) as a common framework.
Results
15 people with CD with a median age of 46 years (IQR 34–60) and median disease duration of 15 years (IQR 8–30) participated. Self-efficacy, social support, job satisfaction and occupational balance were mentioned most frequently. While participation appeared to have greater meaning to men, appreciation and resilience seemed to be more important for women. Of 18 PROs the Perceived Stress Questionnaire (PSQ), the Inflammatory Bowel disease — Self-efficacy scale (IBD-SES), the Life Orientation Test — Revised (LOT-R) and the Patient Activation Measure 13 (PAM-13) cover most DHs.
Conclusions
This is the first study elaborating the coverage of patient's perspective by commonly used PROs in CD. The findings could support health professionals to focus on DHs in people with CD in clinical practice and research.
doi:10.1016/j.crohns.2012.12.014
PMCID: PMC3889494  PMID: 23375212
DH, determinant of health; DHs, determinants of health; HP, health promotion; Crohn's disease; Determinants of health; Health and wellbeing; Health promotion; Inflammatory bowel disease; Patient-reported outcomes
7.  Patient education, disease activity and physical function: can we be more targeted? A cross sectional study among people with rheumatoid arthritis, psoriatic arthritis and hand osteoarthritis 
Arthritis Research & Therapy  2013;15(5):R156.
Introduction
In order to target educational needs of patients more effectively, an Austrian-German educational needs assessment tool (OENAT) was developed, the educational needs of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and hand osteoarthritis (HOA) were described and the relationships between educational needs, gender, disease activity and function were explored.
Methods
The English ENAT was adapted into Austrian-German using Beaton's cross-cultural adaptation process. Internal construct validity was assessed by Rasch analysis. Educational needs across diagnostic groups and subgroups of patients were summarized descriptively and their relationship with disease activity and physical functioning explored.
Results
The sample comprised 130 RA, 125 PsA and 48 HOA patients. Their mean ages ± SD were 56 ± 14, 51 ± 11 and 64 ± 7 years for RA, PsA and HOA; disease duration was 11 ± 9, 11 ± 11 and 14 ± 9 years, respectively. More than 70% in each patient group expressed interest in receiving education about their disease.
The educational needs differed significantly between women and men in all 3 groups. In RA and PsA, female patients expressed significantly higher educational needs than men in 'movements’ and 'feelings’ domains (p=0.04 and p=0.03 for RA and p<0.01 and p=0.01 for PsA). Female patients in the HOA group had significantly higher scores on all domains except for the 'movements’. Older patients with PsA scored significantly higher than their younger counterparts in the 'pain’ domain (p=0.05). RA patients with disease duration >5 years), expressed higher educational needs in 'movements’ (p<0.01). Educational background had effects in the PsA group only, patients with basic education had greater scores than those with higher education on 'movements’ and 'arthritis process’ (p=0.01).
In the RA group, DAS28 correlated significantly with 'movements’ (r=0.24, p=0.01), 'feelings’ (r=0.22, p=0.02), and 'treatments’ (r=0.22, p=0.03). In the PsA group, all OENAT domains correlated with disease activity (DAPSA and CDAI).
Conclusions
This study showed that educational needs vary with personal characteristics. Patient education may be more targeted and effective, if gender, age, educational background and disease duration are taken into account. Correlations with disease activity and function suggest that the OENAT could enable identification of 'intervention points’, which can be ideal opportunities for effective patient education.
doi:10.1186/ar4339
PMCID: PMC3978882  PMID: 24286444
8.  B-cell targeted therapeutics in clinical development 
Arthritis Research & Therapy  2013;15(Suppl 1):S4.
B lymphocytes are the source of humoral immunity and are thus a critical component of the adaptive immune system. However, B cells can also be pathogenic and the origin of disease. Deregulated B-cell function has been implicated in several autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. B cells contribute to pathological immune responses through the secretion of cytokines, costimulation of T cells, antigen presentation, and the production of autoantibodies. DNA-and RNA-containing immune complexes can also induce the production of type I interferons, which further promotes the inflammatory response. B-cell depletion with the CD20 antibody rituximab has provided clinical proof of concept that targeting B cells and the humoral response can result in significant benefit to patients. Consequently, the interest in B-cell targeted therapies has greatly increased in recent years and a number of new biologics exploiting various mechanisms are now in clinical development. This review provides an overview on current developments in the area of B-cell targeted therapies by describing molecules and subpopulations that currently offer themselves as therapeutic targets, the different strategies to target B cells currently under investigation as well as an update on the status of novel therapeutics in clinical development. Emerging data from clinical trials are providing critical insight regarding the role of B cells and autoantibodies in various autoimmune conditions and will guide the development of more efficacious therapeutics and better patient selection.
doi:10.1186/ar3906
PMCID: PMC3624127  PMID: 23566679
9.  Cadherin-11 Promotes Invasive Behavior of Fibroblast-like Synoviocytes 
Arthritis and rheumatism  2009;60(5):1305-1310.
Objective
To define the expression pattern of cadherin-11 in destructive pannus tissue of patients with rheumatoid arthritis and to determine if cadherin-11 expression in fibroblast-like synoviocytes controls their invasive capacity.
Methods
Cadherin-11 expression in rheumatoid synovial tissue was evaluated using immunohistochemistry. To examine the role of cadherin-11 in regulating the invasive behavior of fibroblast-like synoviocytes, we generated L-cell clones expressing wild-type cadherin-11, mutant cadherin-11, and empty vector transfected controls. The invasive capacity of L-cell transfectants and cultured fibroblast-like synoviocytes treated with a blocking cadherin-11-Fc protein or control immunoglobulin was determined in Matrigel invasion assays.
Results
Immunohistochemistry revealed that cadherin-11 is abundantly expressed in cells at the cartilage-pannus junction in rheumatoid synovitis. Invasion assays demonstrate a twofold increased invasive capacity of cadherin-11 transfected L-cells compared to L-cells transfected with E-cadherin or control vector. The invasive behavior of the L-cells stably transfected with a cadherin-11 construct that lacked the juxta-membrane cytoplasmic domain (cadherin-11 ΔJMD) was diminished to the level of vector control L-cells. Further, treatment with the cadherin-11-Fc fusion protein diminished the invasive capacity of fibroblast-like synoviocytes.
Conclusion
These in vitro studies implicate a role for cadherin-11 in promoting cell invasion and contribute insight into the invasive nature of fibroblast-like synoviocytes in chronic synovitis and rheumatoid arthritis.
doi:10.1002/art.24453
PMCID: PMC3764540  PMID: 19404963
Cadherin-11; Fibroblast-like Synoviocytes; Cell Invasion
10.  Golimumab in patients with active rheumatoid arthritis who have previous experience with tumour necrosis factor inhibitors: results of a long-term extension of the randomised, double-blind, placebo-controlled GO-AFTER study through week 160 
Annals of the Rheumatic Diseases  2012;71(10):1671-1679.
Objective
The aim of this study was to assess long-term golimumab therapy in patients with rheumatoid arthritis (RA) who discontinued previous tumour necrosis factor alpha (TNFα) inhibitor(s) for any reason.
Methods
Results through week 24 of this multicentre, randomised, double-blind, placebo-controlled study of active RA (≥4 tender, ≥4 swollen joints) were previously reported. Patients received placebo (Group 1), 50 mg golimumab (Group 2) or 100 mg golimumab (Group 3) subcutaneous injections every 4 weeks. Patients from Groups 1 and 2 with <20% improvement in tender/swollen joints at week 16 early escaped to golimumab 50 mg and 100 mg, respectively. At week 24, Group 1 patients crossed over to golimumab 50 mg, Group 2 continued golimumab 50/100 mg per escape status and Group 3 maintained dosing. Data through week 160 are reported.
Results
459 of the 461 randomised patients were treated; 236/459 (51%) continued treatment through week 160. From week 24 to week 100, ACR20 (≥20% improvement in American College of Rheumatology criteria) response and ≥0.25 unit HAQ (Health Assessment Questionnaire) improvement were sustained in 70–73% and 75–81% of responding patients, respectively. Overall at week 160, 63%, 67% and 57% of patients achieved ACR20 response and 59%, 65% and 64% had HAQ improvement ≥0.25 unit in Groups 1, 2 and 3, respectively. Adjusted for follow-up duration, adverse event incidences (95% CI) per 100 patient-years among patients treated with golimumab 50 mg and 100 mg were 4.70 (2.63 to 7.75) and 8.07 (6.02 to 10.58) for serious infection, 0.95 (0.20 to 2.77) and 2.04 (1.09 to 3.49) for malignancy and 0.00 (0.00 to 0.94) and 0.62 (0.17 to 1.59) for death, respectively.
Conclusion
In patients with active RA who discontinued previous TNF-antagonist treatment, golimumab 50 and 100 mg injections every 4 weeks yielded sustained improvements in signs/symptoms and physical function in ∼57–67% of patients who continued treatment. Golimumab safety was consistent with other anti-TNF agents, although definitive conclusions regarding long-term safety require further monitoring.
doi:10.1136/annrheumdis-2011-200956
PMCID: PMC3439650  PMID: 22459542
11.  A Dynamic Real Time In Vivo and Static Ex Vivo Analysis of Granulomonocytic Cell Migration in the Collagen-Induced Arthritis Model 
PLoS ONE  2012;7(4):e35194.
Neutrophilic granulocytes and monocytes (granulomonocytic cells; GMC) drive the inflammatory process at the earliest stages of rheumatoid arthritis (RA). The migratory behavior and functional properties of GMC within the synovial tissue are, however, only incompletely characterized. Here we have analyzed GMC in the murine collagen-induced arthritis (CIA) model of RA using multi-photon real time in vivo microscopy together with ex vivo analysis of GMC in tissue sections.
GMC were abundant as soon as clinical arthritis was apparent. GMC were motile and migrated randomly through the synovial tissue. In addition, we observed the frequent formation of cell clusters consisting of both neutrophilic granulocytes and monocytes that actively contributed to the inflammatory process of arthritis. Treatment of animals with a single dose of prednisolone reduced the mean velocity of cell migration and diminished the overall immigration of GMC.
In summary, our study shows that the combined application of real time in vivo microscopy together with elaborate static post-mortem analysis of GMC enables the description of dynamic migratory characteristics of GMC together with their precise location in a complex anatomical environment. Moreover, this approach is sensitive enough to detect subtle therapeutic effects within a very short period of time.
doi:10.1371/journal.pone.0035194
PMCID: PMC3329447  PMID: 22529989
12.  Value of self-performed joint counts in rheumatoid arthritis patients near remission 
Introduction
To determine the validity and reliability of patients' self-performed joint counts compared to joint counts by professional assessors in rheumatoid arthritis (RA) patients in different disease activity states.
Methods
In patients with established RA we determined the inter-rater reliability of joint counts performed by an independent evaluator and the patient using intraclass correlation (ICC), and agreement on activity in individual joints by kappa statistics. We also performed longitudinal analyses to assess consistency of assessments over time. Finally, we investigated the concordance of joint counts of different assessors in patients with different levels of disease activity.
Results
The reliability of patient self-performed joint counts was high when compared to independent objective assessment (ICC; 95%confidence interval (CI)) for the assessment of swelling (0.32; 0.15 to 0.46) and tenderness (0.75; 0.66 to 0.81), with higher agreement for larger joints (kappa: 0.57 and 0.45, respectively) compared to smaller joints (metacarpo-phalangeal joint (MCPs): 0.31 and 0.45; and proximal interphalangeal joint (PIPs): 0.22 and 0.47, for swelling and tenderness, respectively).
Patients in remission according to the Simplified Disease Activity Index (SDAI ≤ 3.3) showed better concordance of the joint counts (swollen joint count (SJC) ties 25/37, tender joint count (TJC) ties 26/37) compared to moderate/high disease activity states (SDAI > 11; MDA/HDA: SJC ties 9/72, TJC ties 21/72). Positive and negative predictive values regarding the presence of SDAI remission were reasonably good (0.86 and 0.95, respectively). A separate training session for patients did not improve the reliability of joint assessment. The results were consistent in the longitudinal analyses.
Conclusions
Self-performed joint counts are particularly useful for monitoring in patients having attained remission, as these patients seem able to detect state of remission.
doi:10.1186/ar3777
PMCID: PMC3446429  PMID: 22417647
13.  American College of Rheumatology/European League against Rheumatism Preliminary Definition of Remission in Rheumatoid Arthritis for Clinical Trials 
Arthritis and rheumatism  2011;63(3):573-586.
Background
With remission in rheumatoid arthritis (RA) an increasingly attainable goal, there is no widely used definition of remission that is stringent but achievable and could be applied uniformly as an outcome in clinical trials.
Methods
A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism and the Outcome Measures in Rheumatology Initiative (OMERACT) met to guide the process and review prespecified analyses from clinical trials of patients with RA. The committee requested a stringent definition (little, if any, active disease) and decided to use core set measures to define remission including at least joint counts and an acute phase reactant. Members were surveyed to select the level of each core set measure consistent with remission. Candidate definitions of remission were tested including those that constituted a number of individual measures in remission (Boolean approach) as well as definitions using disease activity indexes. To select a definition of remission, trial data were analyzed to examine the added contribution of patient reported outcomes and the ability of candidate measures to predict later good x-ray and functional outcomes.
Results
Survey results for the definition of remission pointed to indexes at published thresholds and to a count of core set measures with each measure scored as 1 or less (e.g. tender and swollen joint counts, CRP and global assessments on 0-10 scale). Analyses suggested the need to include a patient reported measure. Examination of 2 year follow-up data suggested that many candidate definitions performed comparably in terms of predicting later good x-ray and functional outcomes, although DAS28 based measures of remission did not predict good radiographic outcomes as well as did the other candidate definitions. Given these and other considerations, we propose that a patient be defined as in remission based on one of two definitions : 1: When their scores on the following measures are all <1: tender joint count, swollen joint count, CRP (in mg/dL) and patient global assessment (0-10 scale), OR 2: when their score on the SDAI is < 3.3.
Conclusion
We propose two new definitions of remission both of which can be uniformly applied and widely used in RA clinical trials. We recommend that one of these be selected in each trial as an outcome and that the results on both be reported in each trial.
doi:10.1002/art.30129
PMCID: PMC3115717  PMID: 21294106
15.  The 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritis 
Arthritis and rheumatism  2010;62(9):2582-2591.
Objective
The American College of Rheumatology and the European League Against Rheumatism have developed new classification criteria for rheumatoid arthritis (RA). The aim of Phase 2 of the development process was to achieve expert consensus on the clinical and laboratory variables that should contribute to the final criteria set.
Methods
Twenty-four expert RA clinicians (12 from Europe and 12 from North America) participated in Phase 2. A consensus-based decision analysis approach was used to identify factors (and their relative weights) that influence the probability of “developing RA,” complemented by data from the Phase 1 study. Patient case scenarios were used to identify and reach consensus on factors important in determining the probability of RA development. Decision analytic software was used to derive the relative weights for each of the factors and their categories, using choice-based conjoint analysis.
Results
The expert panel agreed that the new classification criteria should be applied to individuals with undifferentiated inflammatory arthritis in whom at least 1 joint is deemed by an expert assessor to be swollen, indicating definite synovitis. In this clinical setting, they identified 4 additional criteria as being important: number of joints involved and site of involvement, serologic abnormality, acute-phase response, and duration of symptoms in the involved joints. These criteria were consistent with those identified in the Phase 1 data-driven approach.
Conclusion
The consensus-based, decision analysis approach used in Phase 2 complemented the Phase 1 efforts. The 4 criteria and their relative weights form the basis of the final criteria set.
doi:10.1002/art.27580
PMCID: PMC3077961  PMID: 20872596
16.  Concepts of functioning and health important to people with systemic sclerosis: a qualitative study in four European countries 
Annals of the Rheumatic Diseases  2011;70(6):1074-1079.
Objective
To describe the experiences of people with systemic sclerosis (SSc) in different European countries of functioning and health and to link these experiences to the WHO International Classification of Functioning, Disability and Health (ICF) to develop a common understanding from a bio-psycho-social perspective.
Method
A qualitative multicentre study with focus-group interviews was performed in four European countries: Austria, Romania, Sweden and Switzerland. The qualitative data analysis followed a modified form of ‘meaning condensation’ and the concepts that emerged in the analysis were linked to the ICF.
Results
63 people with SSc participated in 13 focus groups. In total, 86 concepts were identified. 32 (37%) of these were linked to the ICF component body functions and structures, 21 (24%) to activities and participation, 26 (30%) to environmental factors, 6 (7%) to personal factors and 1 (1%) to the health condition itself. 19 concepts (22%) were identified in all four countries and included impaired hand function, household activities, paid work, drugs, climate and coldness, support from others and experiences with healthcare institutions, non-pharmacological treatment, social security and benefits.
Conclusion
Concepts identified in all four countries could be used for guiding clinical assessment, as well as interdisciplinary team care and rheumatological rehabilitation for patients with SSc. For a full understanding of the aspects of the disease that were most relevant to people with SSc, people with SSc from multiple countries needed to be involved.
doi:10.1136/ard.2010.148767
PMCID: PMC3086051  PMID: 21540204
17.  Infliximab: 12 years of experience 
Arthritis Research & Therapy  2011;13(Suppl 1):S2.
Rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are immune-mediated conditions that share an inflammatory mechanism fuelled by excessive cytokines, particularly TNF. Control of inflammation and rapid suppression of cytokines are important in treating these diseases. With this understanding and the corresponding advent of TNF inhibitors, RA patients, AS patients and PsA patients have found more choices than ever before and have greater hope of sustained relief. As a widely used TNF inhibitor, infliximab has a deep and established record of efficacy and safety data. Extensive evidence - from randomised controlled clinical trials, large registries and postmarketing surveillance studies - shows that infliximab effectively treats the signs and symptoms, provides rapid and prolonged suppression of inflammation, prevents radiologically observable disease progression and offers an acceptable safety profile in RA, AS and PsA. In very recent studies, investigators have observed drug-free remission in some patients. Additionally, infliximab may interfere with rapidly progressing disease in RA by early addition to methotrexate in patients with signs of an aggressive course. Finally, infliximab has been shown to reduce PsA clinical manifestations such as nail involvement. With our current understanding, substantial data and increasing confidence regarding use in practice, infliximab can be considered a well-known drug in our continued campaign against inflammatory rheumatic diseases.
doi:10.1186/1478-6354-13-S1-S2
PMCID: PMC3123963  PMID: 21624181
18.  Certolizumab pegol plus methotrexate provides broad relief from the burden of rheumatoid arthritis: analysis of patient-reported outcomes from the RAPID 2 trial 
Annals of the Rheumatic Diseases  2011;70(6):996-1002.
Objective
To assess the impact of certolizumab pegol (CZP) on patient-reported outcomes (PROs) in rheumatoid arthritis (RA), and to interpret these results using number needed to treat (NNT), and associations between PRO responses and longer term outcomes.
Methods
A total of 619 patients with active RA were randomised to CZP 200 or 400 mg, or placebo plus methotrexate (MTX). PROs assessed included pain, patient's global assessment of disease activity (PtGA), physical function, fatigue and health-related quality of life. Treatment impact on PROs, NNT to achieve simultaneous improvements in multiple PROs and correlations between PROs were calculated. Times to onset of improvements greater than or equal to minimum clinically important differences (MCIDs) in pain as a determinant of clinical outcomes at week 24 were compared between week 6 and 12 responders, and in patients with improvements in pain ≥MCID at week 12 (week 12 responders/non-responders).
Results
CZP 200 and 400 mg plus MTX were associated with rapid, clinically meaningful improvements in all PROs. The NNT for subjects to report changes ≥MCID in up to five PROs was two to three, and five for all six PROs (pain, PtGA, physical function, fatigue and short-form 36-item Physical and Mental Component Summary Scores). More patients with improvements ≥MCID in pain at week 6 than those at week 12 had lower disease activity at week 24. Week 12 pain responders had better clinical outcomes at week 24 than non-responders.
Conclusions
The data demonstrate that CZP provides broad relief from the burden of RA.
Trial registration number
NCT00160602.
doi:10.1136/ard.2010.143586
PMCID: PMC3086050  PMID: 21415050
19.  Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis 
Annals of the Rheumatic Diseases  2011;70(6):909-920.
Background
Since initial approval for the treatment of rheumatoid arthritis (RA), rituximab has been evaluated in clinical trials involving various populations with RA. Information has also been gathered from registries. This report therefore updates the 2007 consensus document on the use of rituximab in the treatment of RA.
Methods
Preparation of this new document involved many international experts experienced in the treatment of RA. Following a meeting to agree upon the core agenda, a systematic literature review was undertaken to identify all relevant data. Data were then interrogated by a drafting committee, with subsequent review and discussion by a wider expert committee leading to the formulation of an updated consensus statement. These committees also included patients with RA.
Results
The new statement covers wide-ranging issues including the use of rituximab in earlier RA and impact on structural progression, and aspects particularly pertinent to rituximab such as co-medication, optimal dosage regimens, repeat treatment cycles and how to manage non-response. Biological therapy following rituximab usage is also addressed, and safety concerns including appropriate screening for hepatitis, immunoglobulin levels and infection risk. This consensus statement will support clinicians and inform patients when using B-cell depletion in the management of RA, providing up-to-date information and highlighting areas for further research.
Conclusion
New therapeutic strategies and treatment options for RA, a chronic destructive and disabling disease, have expanded over recent years. These have been summarised in general strategic suggestions and specific management recommendations, emphasising the importance of expedient disease-modifying antirheumatic drug implementation and tight disease control. This consensus statement is in line with these fundamental principles of management.
doi:10.1136/ard.2010.144998
PMCID: PMC3086093  PMID: 21378402
20.  Endothelial progenitor cells in active rheumatoid arthritis: effects of tumour necrosis factor and glucocorticoid therapy 
Annals of the Rheumatic Diseases  2007;66(10):1284-1288.
Objectives
To study the effects of short‐term intermediate dose glucocorticoid (GC) therapy in patients with active rheumatoid arthritis (RA) on circulating endothelial progenitor cells (EPC), which are known to influence cardiovascular risk, and to elucidate mechanisms potentially responsible for the reduction of EPCs in patients with active RA.
Methods
EPCs were quantified in 29 patients with active RA by flow cytometry, colony forming unit (CFU) and circulating angiogenic cell (CAC) assays before and after 7 days of intermediate dose GC therapy. CFU from patients with RA and from healthy referents (HR) were cultured in vitro in the absence or presence of dexamethasone (Dex) and/or TNF.
Results
After 1 week of GC therapy, EPC increased from 0.026 (SD 0.003)% to 0.053 (SD 0.010)% (p<0.01), and from 12 (SD 4) to 27 (SD 7) CFU/well (p<0.02); CAC also increased from 7 (SD 2) to 29 (SD 8) cells/high power field (p<0.05). In parallel, disease activity decreased significantly after GC treatment. TNF serum levels also decreased from 36 (SD 10) to 14 (SD 6) pg/ml (p<0.0001). Addition of Dex to the RA CFU led to a significant increase of mean CFU counts, whereas addition of TNF induced a decrease of CFU.
Conclusions
Our data indicate that TNF may be at least partly responsible for the reduction of EPC seen in patients with RA. Intermediate doses of GCs for a short period of time, apart from reducing disease activity, significantly increase circulating EPC.
doi:10.1136/ard.2006.066605
PMCID: PMC1994291  PMID: 17293363
21.  The appropriate use of non-steroidal anti-inflammatory drugs in rheumatic disease: opinions of a multidisciplinary European expert panel 
Annals of the Rheumatic Diseases  2010;70(5):818-822.
Introduction
Given the safety issues of non-steroidal anti-inflammatory drugs (NSAID) and the robustness of guidelines, making treatment choices in daily clinical practice is increasingly difficult. This study aimed systematically to analyse the opinions of a multidisciplinary European expert panel on the appropriateness of different NSAID, with or without the use of a proton pump inhibitor (PPI), in individual patients with chronic rheumatic disease.
Methods
Using the Research and Development/University of California at Los Angeles appropriateness method, the appropriateness of five (non-)selective NSAID with or without a PPI was assessed for 144 hypothetical patient profiles, ie, unique combinations of cardiovascular and gastrointestinal risk factors. Appropriateness statements were calculated for all indications.
Results
All options without PPI were considered appropriate in patients with no gastrointestinal/cardiovascular risk factors. Cyclooxygenase-2 selective inhibitors (C2SI) alone and non-selective NSAID plus PPI were preferred for patients with elevated gastrointestinal risk and low cardiovascular risk. Naproxen plus PPI was favoured in patients with high cardiovascular risk. For the combination of high gastrointestinal/high cardiovascular risk the use of any NSAID was discouraged; if needed, naproxen plus PPI or a C2SI plus PPI could be considered.
Discussion
The panel results may support treatment considerations at the level of individual patients, according to their gastrointestinal/cardiovascular risk profile.
doi:10.1136/ard.2010.128660
PMCID: PMC3070276  PMID: 20833736
22.  Research in hand osteoarthritis: time for reappraisal and demand for new strategies. An opinion paper 
Annals of the Rheumatic Diseases  2007;66(9):1157-1161.
Background
Osteoarthritis of the hands is a prevalent musculoskeletal disease with a considerable effect on patients' lives, but knowledge and research results in the field of hand osteoarthritis are limited. Therefore, the Disease Characteristics in Hand OA (DICHOA) initiative was founded in early 2005 with the aim of addressing key issues and facilitating research into hand osteoarthritis.
Objective
To review and discuss current knowledge on hand osteoarthritis with regard to aetiopathogenesis, diagnostic criteria, biomarkers and clinical outcome measures.
Methods
Recommendations were made based on a literature review.
Results
Outcomes of hand osteoarthritis should be explored, including patient perspective on the separate components of disease activity, damage and functioning. All imaging techniques should be cross‐validated for hand osteoarthritis with clinical status, including disease activity, function and performance, biomarkers and long‐term outcome. New imaging modalities are available and need scoring systems and validation. The role of biomarkers in hand osteoarthritis has to be defined.
Conclusion
Future research in hand osteoarthritis is warranted.
doi:10.1136/ard.2007.070813
PMCID: PMC1955144  PMID: 17360780
osteoarthritis; hand; outcome measures; biomarkers; imaging
23.  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
24.  The public neglect of rheumatic diseases: insights from analyses of attendees in a musculoskeletal disease awareness activity 
Annals of the Rheumatic Diseases  2007;66(5):697-699.
Objectives
To obtain data on the care received by individuals counselled during a public health awareness campaign on painful musculoskeletal conditions (MSC).
Methods
Easy non‐formal access to rheumatologists/pain specialists was offered using a mobile unit (Rheuma‐Bus) at widely accessible sites. Clients were asked to assess their severity of pain using a 100 mm visual analogue scale (VAS). Age, gender, disease duration, diagnosis if known, current and previous treatment as well as tentative diagnoses assigned and recommendations given to each individual by the counselling physicians were recorded.
Results
Average (SD) VAS pain rating was 59 (20.6) mm. Approximately 40% of clients had never consulted a physician for their condition before, but had lower pain scores than those who had seen a physician. Patients with inflammatory MSC had higher pain scores than those with non‐inflammatory conditions. More than 2% of the clients had a newly detected inflammatory rheumatic disease.
Conclusions
Many individuals having painful MSC seek medical help only when a very high threshold of pain is reached. Even while under treatment, the high mean pain scores suggest neglect of MSC that are not adequately recognised as important contributors to disability and decreased quality of life.
doi:10.1136/ard.2006.062422
PMCID: PMC1954619  PMID: 17204565
25.  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

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