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1.  Minimal clinically important improvement/difference (MCII/MCID) and patient acceptable symptom state (PASS): what do these concepts mean? 
Annals of the Rheumatic Diseases  2007;66(Suppl 3):iii40-iii41.
An increasing focus has over recent years been directed to the use of categorical endpoints to define response, i.e. to define cut‐points for important improvement and/or acceptable clinical state. The levels of Minimal Clinically Important Improvement (MCII) are typically defined according to the patients perception of what is an important improvement. It can be defined as the smallest change in measurement that signifies an important improvement. MCII signifies an improvement of relevance in a clinical trial, or the minimal meaningful change at an individual level. The Minimal Clinically Important Difference (MCID) may reflect either an improvement or a worsening. Patient Acceptable Symptom State (PASS) has been defined as the highest level of symptom beyond which patients consider themselves well. Cut‐points for MCII and PASS are usually identified through two different statistical approaches. The 75th percentage approach identifies the cut‐point corresponding to the 75 percentile of the scores for improvement in patients who report an important improvement by the anchoring question. Applying receiver operating characteristic (ROC) curves allows for choosing the threshold that is the best compromise between sensitivity and specificity for each outcome criterion.
The identified cut‐points for MCII and PASS may easily be incorporated as endpoints in clinical trials, and will provide information about the proportion of patients that achieve an improvement exceeding the level accepted as MCII and achieve a state accepted as PASS.
PMCID: PMC2095292  PMID: 17934093
2.  Introduction of a novel magnetic resonance imaging tenosynovitis score for rheumatoid arthritis: reliability in a multireader longitudinal study 
Annals of the Rheumatic Diseases  2007;66(9):1216-1220.
To describe a novel scoring system for the assessment of tenosynovitis by magnetic resonance imaging (MRI) in patients with rheumatoid arthritis, and assess its intra‐ and inter‐reader reliability in a multireader, longitudinal setting.
Flexor and extensor tenosynovitis were evaluated at the level of the wrist in 10 different anatomical areas, graded semi‐quantitatively from grade 0 to 3 (total score 0–30), based on the maximum width of post‐contrast enhancement within each anatomical area on axial T1‐weighted MR images. Ten sets of baseline and 1‐year follow‐up MR images of the wrists of patients with rheumatoid arthritis with early and established disease were scored independently by four readers twice on 2 consecutive days. Intra‐ and inter‐reader agreements were evaluated.
The intrareader intraclass correlation coefficients (ICCs) were high for status scores (median ICCs 0.84–0.88) and slightly lower for change score (0.74). The smallest detectable difference (SDD) in % of the maximum score was 11.2–11.5% for status scores and 13.3% for change scores. Inter‐reader single‐measure ICCs were acceptable for both status scores (median 0.73–0.74) and change scores (0.67), while average‐measures ICCs were very high for both status and change score (all ⩾0.94). The median scoring time per patient (baseline and follow‐up images) was 7 min (range 3–10).
The introduced tenosynovitis scoring system demonstrates a high degree of multireader reliability, is feasible, and may be used as an adjuvant to the existing OMERACT RAMRIS score, allowing improved quantification of inflammatory soft tissue changes in patients with rheumatoid arthritis.
PMCID: PMC1955157  PMID: 17392347
3.  Calprotectin (a major leucocyte protein) is strongly and independently correlated with joint inflammation and damage in rheumatoid arthritis 
Annals of the Rheumatic Diseases  2007;66(8):1093-1097.
Calprotectin is a major leucocyte protein, shown to correlate well with laboratory and clinical assessments in several inflammatory rheumatic diseases, and large concentrations of calprotectin have been found in synovial fluid from patients with rheumatoid arthritis (RA). The objective of the present study was to examine correlations between calprotectin and joint damage.
145 patients with RA were analysed cross sectionally with laboratory (calprotectin, C reactive protein (CRP), and erythrocyte sedimentation rate (ESR)), clinical (28 joint counts (tender, swollen), physician global VAS, DAS28 and RA Articular Damage score (RAAD)), and radiographic (plain hand radiographs; modified Sharp's method) measurements, on the same day.
Calprotectin showed a highly significant correlation with measures of joint damage; modified Sharp score r = 0.43 (p<0.001) and RAAD r = 0.40 (p<0.001). The association with modified Sharp score and RAAD score was maintained after adjustment for CRP, ESR, rheumatoid factor, DAS28, sex, and age in a multiple regression analysis (p = 0.018 and p = 0.04, respectively), while neither CRP nor ESR showed any independent associations. Highly significant correlations (p<0.001) were also found between calprotectin and both laboratory and clinical markers of inflammation.
Calprotectin was found to significantly and independently explain the variation in the radiological and clinical assessments of joint damage. Longitudinal studies are required to examine whether calprotectin may predict the progression of joint damage in RA.
PMCID: PMC1954700  PMID: 17234650
calprotectin; rheumatoid arthritis; joint inflammation; joint damage; radiographs
4.  Updating the OMERACT Filter: Core Areas as a basis for defining core outcome sets 
The Journal of rheumatology  2014;41(5):994-999.
The OMERACT Filter provides guidelines for the development and validation of outcome measures for use in clinical research. The ‘Truth’ section of the OMERACT Filter pre-supposes an explicit framework for identifying the relevant core outcomes that are universal to all studies of the effects of intervention effects. There is no published outline for instrument choice or development that is aimed at measuring outcome, was derived from broad consensus over its underlying philosophy, or includes a structured and documented critique. Therefore, a new proposal for defining core areas of measurement (“Filter 2.0 Core Areas of Measurement”) was presented at OMERACT 11 to explore areas of consensus and consider whether already endorsed core outcome sets fit in to this newly proposed framework.
Discussion groups critically reviewed the extent to which case studies of current OMERACT Working Groups complied with or negated the proposed framework, whether these observations had a more general application, and what issues remained to be resolved.
Although there was a broad acceptance of the framework in general, several important areas of construction, presentation and clarity of the framework were questioned. The discussion groups and subsequent feedback highlighted 20 such issues.
These issues will require resolution in order to reach consensus on accepting the proposed Filter 2.0 framework of Core Areas as the basis for the selection of Core Outcome Domains and hence appropriate Core Outcome Sets for clinical trials.
PMCID: PMC4217644  PMID: 24634204
5.  Updating the OMERACT Filter: Implications of Filter 2.0 to select outcome instruments through assessment of ‘Truth’: content, face and construct validity 
The Journal of rheumatology  2014;41(5):1000-1004.
The OMERACT Filter provides guidelines for the development and validation of outcome measures for use in clinical research. The ‘Truth’ section of the OMERACT Filter requires that criteria be met to demonstrate that the outcome instrument meets the criteria for content, face and construct validity.
Discussion groups critically reviewed the variety of ways in which case studies of current OMERACT Working Groups complied with the ‘Truth’ component of the Filter and what issues remained to be resolved.
The case studies showed that there is broad agreement on criteria for meeting the ‘Truth’ criteria through demonstration of content, face and construct validity; however several issues were identified that the Filter Working Group will need to address.
These issues will require resolution in order to reach consensus on how ‘Truth’ will be assessed for the proposed Filter 2.0 framework, for instruments to be endorsed by OMERACT.
PMCID: PMC4212637  PMID: 24692531
7.  The 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritis 
Arthritis and rheumatism  2010;62(9):2582-2591.
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.
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.
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.
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.
PMCID: PMC3077961  PMID: 20872596
8.  Efficacy of High Intensity Exercise on Disease Activity and Cardiovascular Risk in Active Axial Spondyloarthritis: A Randomized Controlled Pilot Study 
PLoS ONE  2014;9(9):e108688.
Physical therapy is recommended for the management of axial spondyloarthritis (axSpA) and flexibility exercises have traditionally been the main focus. Cardiovascular (CV) diseases are considered as a major health concern in axSpA and there is strong evidence that endurance and strength exercise protects against CV diseases. Therefore, the aim of this study was to investigate the efficacy of high intensity endurance and strength exercise on disease activity and CV health in patients with active axSpA.
In a single blinded randomized controlled pilot study the exercise group (EG) performed 12 weeks of endurance and strength exercise while the control group (CG) received treatment as usual. The primary outcome was the Ankylosing Spondylitis (AS) Disease Activity Score (ASDAS). Secondary outcomes included patient reported disease activity (Bath AS Disease Activity Index [BASDAI]), physical function (Bath AS Functional Index [BASFI]), and CV risk factors measured by arterial stiffness (Augmentation Index [Alx]) and Pulse Wave Velocity [PWV]), cardiorespiratory fitness (VO2 peak) and body composition. ANCOVA on the post intervention values with baseline values as covariates was used to assess group differences, and Mann Whitney U-test was used for outcomes with skewed residuals.
Twenty-eight patients were included and 24 (EG, n = 10, CG, n = 14) completed the study. A mean treatment effect of −0.7 (95%CI: −1.4, 0.1) was seen in ASDAS score. Treatment effects were also observed in secondary outcomes (mean group difference [95%CI]): BASDAI: −2.0 (−3.6, −0.4), BASFI: −1.4 (−2.6, −0.3), arterial stiffness (estimated median group differences [95% CI]): AIx (%): −5.3 (−11.0, −0.5), and for PVW (m/s): −0.3 (−0.7, 0.0), VO2 peak (ml/kg/min) (mean group difference [95%CI]: 3.7 (2.1, 5.2) and trunk fat (%): −1.8 (−3.0, −0.6). No adverse events occurred.
High intensity exercise improved disease activity and reduced CV risk factors in patients with active axSpA. These effects will be further explored in a larger trial.
Trial Registration NCT01436942
PMCID: PMC4182541  PMID: 25268365
9.  Associations between the PTPN22 1858C→T polymorphism and radiographic joint destruction in patients with rheumatoid arthritis: results from a 10‐year longitudinal study 
Annals of the Rheumatic Diseases  2007;66(12):1604-1609.
To investigate whether the PTPN22 1858T risk variant is associated with the rate of radiographic progression in rheumatoid arthritis (RA).
A longitudinally followed cohort of 238 Norwegian patients with RA (the EURIDISS cohort) was genotyped for the PTPN22 1858C→T polymorphism. Radiographic damage was assessed by hand radiographs at baseline and after 1, 2, 5 and 10 years, and the radiographs were scored with the Sharp method modified by van der Heijde (Sharp–van der Heijde score) by a single experienced reader. Baseline serum levels of rheumatoid factor and anti‐cyclic citrullinated peptide autoantibodies were also examined.
The reported association between RA susceptibility and carriage of the T allele (34.4% in patients vs 21.4% in controls; odds ratio 1.92, 95% confidence interval 1.36 to 2.71, p = 0.0002) was confirmed. An association between annual progression rate of Sharp–van der Heijde score and T‐allele carriers (p = 0.01),was also found, which was also present when only patients positive for the shared epitope were analysed (p = 0.03). This association was also maintained in multivariate analyses adjusting for shared epitope and demographic variables.
An association between the PTPN22 risk variant and increased progression rate for structural damage was found. The results indicate that the PTPN22 gene may not only be associated with disease susceptibility, but also with disease progression.
PMCID: PMC2095332  PMID: 17472988
rheumatoid arthritis; PTPN22; longitudinal study; radiographic damage; genetic predisposition
10.  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.
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.
To review and discuss current knowledge on hand osteoarthritis with regard to aetiopathogenesis, diagnostic criteria, biomarkers and clinical outcome measures.
Recommendations were made based on a literature review.
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.
Future research in hand osteoarthritis is warranted.
PMCID: PMC1955144  PMID: 17360780
osteoarthritis; hand; outcome measures; biomarkers; imaging
11.  Pain and psychological health status over a 10‐year period in patients with recent onset rheumatoid arthritis 
Annals of the Rheumatic Diseases  2007;66(9):1195-1201.
To examine rheumatoid arthritis (RA) with short disease duration over 10 years, and to identify factors that are associated with the course of pain, depression and anxiety.
A cohort of 238 patients with RA (age 20–70 years, mean disease duration 2.3 years, 68% rheumatoid factor positive) was followed with assessments at baseline and after 1, 2, 5 and 10 years. Self‐reported health status was assessed by pain on a 100 mm visual analogue scale, the Arthritis Impact Measurement Scales (AIMS), the 28‐item version of General Health Questionnaires, and the Health Assessment Questionnaire. We also examined the erythrocyte sedimentation ratio, grip strength (kg) and radiographic progression of the hands (van der Heijde modified Sharp score). Repeated measures analyses of variance were used to explore the effect of time on measures of outcome among completers, whereas repeated measures analyses using a mixed model were applied to identify factors that were longitudinally associated with pain, depression and anxiety.
At the various assessment points 30% had a visual analogue scale pain score of ⩾40 mm, 5–13% had an AIMS depression score of ⩾4.0 and 20–30% had an AIMS anxiety score of ⩾4.0. The perceived level of pain was explained longitudinally by anxiety, disease activity, physical function and female gender, depression by high disease activity and anxiety, whereas anxiety was explained by low disease activity and depression.
More patients had increased levels of anxiety (20–30%) than increased levels of depression (5–13%). Several factors, including anxiety, but not depression, were associated with the course of pain.
PMCID: PMC1955161  PMID: 17392351
12.  The performance of matrix-based risk models for rapid radiographic progression in BRASS, a cohort of patients with established rheumatoid arthritis 
Arthritis care & research  2013;65(4):526-533.
Matrix-based risk models have been proposed as a tool to predict rapid radiographic progression (RRP) in rheumatoid arthritis (RA), but the experience with such models is limited. We tested the performance of three risk models for RRP in an observational cohort
Subjects from an observational RA cohort with hand radiographs and necessary predictor variables to be classified by the risk models were identified (n=478). RRP was defined as a yearly change in van der Heijde-Sharp score of ≥ 5 units. Patients were placed in the appropriate matrix categories, with a corresponding predicted risk of RRP. The mean predicted probability for cases and non-cases, integrated discrimination improvement, Hosmer-Lemeshow statistics and the c-statistics were calculated.
The median (IQR) age was 59 (50, 66) years, disease duration 12 (4, 23) years and swollen joint count 6 (2, 13), 84% were female and 86% had erosions at baseline. Twelve percent (32/271) of patients treated with synthetic DMARDs at baseline and 10% (21/207) of patients treated with biologic DMARDs experienced RRP. Most of the predictor variables had a skewed distribution in the population. All models had a suboptimal performance when applied to the BRASS cohort, with c-statistics of 0.59 (model A), 0.65 (model B) and 0.57 (model C) and Hosmer-Lemeshow chi-square p-values of 0.06 (model A), 0.005 (model B) and 0.05 (model C).
Matrix risk models developed in clinical trials of patients with early RA had limited ability to predict RRP in this observational cohort of RA patients.
PMCID: PMC3594116  PMID: 23044765
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.
PMCID: PMC3933074  PMID: 24161836
Rheumatoid Arthritis; DMARDs (synthetic); DMARDs (biologic); Treatment; Early Rheumatoid Arthritis
14.  Blocking the effects of interleukin-6 in rheumatoid arthritis and other inflammatory rheumatic diseases: systematic literature review and meta-analysis informing a consensus statement 
Annals of the Rheumatic Diseases  2012;72(4):583-589.
Suppression of the immunoinflammatory cascade by targeting interleukin 6 (IL-6) mediated effects constitutes a therapeutic option for chronic inflammatory diseases. Tocilizumab is the only IL-6 inhibitor (IL-6i) licensed for rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), but also other agents targeting either IL-6 or its receptor are investigated in various indications.
To review published evidence on safety and efficacy of IL-6i in inflammatory diseases.
We performed systematic literature searches in Medline and Cochrane, screened EULAR and American College of Rheumatology meeting-abstracts, and accessed
Comprehensive evidence supports the efficacy of tocilizumab in RA in DMARD-naïve patients, and after DMARD- and TNFi-failure. Randomised comparisons demonstrate superiority of tocilizumab in JIA, but not ankylosing spondylitis (AS). Other indications are currently investigated. Additional IL-6i show similar efficacy; safety generally appears acceptable.
IL-6i is effective and safe in RA and JIA, but not in AS. Preliminary results in other indications need substantiation.
PMCID: PMC3595140  PMID: 23144446
Rheumatoid Arthritis; Juvenile Idiopathic Arthritis; Treatment; DMARDs (biologic)
15.  Prevalence, incidence and progression of hand osteoarthritis in the general population: the Framingham Osteoarthritis Study 
Annals of the rheumatic diseases  2011;70(9):10.1136/ard.2011.150078.
To describe the prevalence and longitudinal course of radiographic, erosive and symptomatic hand osteoarthritis (HOA) in the general population.
Framingham osteoarthritis (OA) study participants obtained bilateral hand radiographs at baseline and 9-year follow-up. The authors defined radiographic HOA at joint level as Kellgren–Lawrence grade (KLG)≥2, erosive HOA as KLG≥2 plus erosion and symptomatic HOA as KLG≥2 plus pain/aching/stiffness. Presence of HOA at individual level was defined as ≥1 affected joint. The prevalence was age-standardised (US 2000 Population 40–84 years).
Mean (SD) baseline age was 58.9 (9.9) years (56.5% women). The age-standardised prevalence of HOA was only modestly higher in women (44.2%) than men (37.7%), whereas the age-standardised prevalence of erosive and symptomatic OA was much higher in women (9.9% vs 3.3%, and 15.9% vs 8.2%). The crude incidence of HOA over 9-year follow-up was similar in women (34.6%) and men (33.7%), whereas the majority of those women (96.4%) and men (91.4%) with HOA at baseline showed progression during follow-up. Incident metacarpophalangeal and wrist OA were rare, but occurred more frequently and from an earlier age in men than women. Development of erosive disease occurred mainly in those with non-erosive HOA at baseline (as opposed to those without HOA), and was more frequent in women (17.3%) than men (9.6%).
The usual female predominance of prevalent and incident HOA was less clear for radiographic HOA than for symptomatic and erosive HOA. With an ageing population, the impact of HOA will further increase.
PMCID: PMC3867970  PMID: 21622766
16.  Hand, hip and knee osteoarthritis in a Norwegian population-based study - The MUST protocol 
Knowledge about the prevalence and consequences of osteoarthritis (OA) in the Norwegian population is limited. This study has been designed to gain a greater understanding of musculoskeletal pain in the general population with a focus on clinically and radiologically confirmed OA, as well as risk factors, consequences, and management of OA.
The Musculoskeletal pain in Ullensaker STudy (MUST) has been designed as an observational study comprising a population-based postal survey and a comprehensive clinical examination of a sub-sample with self-reported OA (MUST OA cohort). All inhabitants in Ullensaker municipality, Norway, aged 40 to 79 years receive the initial population-based postal survey questionnaire with questions about life style, general health, musculoskeletal pain, self-reported OA, comorbidities, health care utilisation, medication use, and functional ability. Participants who self-report OA in their hip, knee and/or hand joints are asked to attend a comprehensive clinical examination at Diakonhjemmet Hospital, Oslo, including a comprehensive medical examination, performance-based functional tests, different imaging modalities, cardiovascular assessment, blood and urine samples, and a number of patient-reported questionnaires including five OA disease specific instruments. Data will be merged with six national data registries. A subsample of those who receive the questionnaire has previously participated in postal surveys conducted in 1990, 1994, and 2004 with data on musculoskeletal pain and functional ability in addition to demographic characteristics and a number of health related factors. This subsample constitutes a population based cohort with 20 years follow-up.
This protocol describes the design of an observational population-based study that will involve the collection of data from a postal survey on musculoskeletal pain, and a comprehensive clinical examination on those with self-reported hand, hip and/or knee OA. These data, in addition to data from national registries, will provide unique insights into clinically and radiologically confirmed OA with respect to risk factors, consequences, and management.
PMCID: PMC3704709  PMID: 23826721
Osteoarthritis; Hand; Hip; Knee; Observational study; Study protocol
17.  Effect of 1-year anti-TNF-α therapy on aortic stiffness, carotid atherosclerosis, and calprotectin in inflammatory arthropathies: a controlled study 
American Journal of Hypertension  2012;25(6):644-650.
Premature arterial stiffening and atherosclerosis are increased in patients with inflammatory arthropathies such as rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). The proinflammatory protein calprotectin is associated with inflammatory arthropathies, vascular pathology, and acute coronary events. We examined the long-term effects of treatment with tumor necrosis factor (TNF)-α antagonists on aortic stiffness and carotid intima media thickness (CIMT) in patients with inflammatory arthropathies, and the relationships to the levels of calprotectin.
Fifty-five patients with RA, AS, or PsA and a clinical indication for anti-TNF-α therapy were included and followed with regular examinations for 1 year. Thirty-six patients starting with anti-TNF-α therapy were compared with a nontreatment group of 19 patients. Examinations included assessments of aortic stiffness (aortic pulse wave velocity, aPWV), CIMT, and plasma calprotectin.
After 1 year, aPWV (mean (s.d.)) was improved in the treatment group, but not in the control group (−0.54 [0.79] m/s vs. 0.06 [0.61] m/s, respectively; P = 0.004), and CIMT progression (median (quartile cut-points, 25th and 75th percentiles)) was reduced in the treatment group compared to the control group (−0.002 [–0.038, 0.030] mm vs. 0.030 [0.011, 0.043] mm, respectively; P = 0.01). In multivariable analyses, anti-TNF-α therapy over time was associated with improved aPWV (P = 0.02) and reduced CIMT progression (P = 0.04), and calprotectin was longitudinally associated with aPWV (P = 0.02).
Long-term anti-TNF-α therapy improved aortic stiffness and CIMT progression in patients with inflammatory arthropathies. Calprotectin may be a soluble biomarker reflecting aortic stiffening in these patients.
PMCID: PMC3635528  PMID: 22378036
anti-TNF-α; arterial stiffness; blood pressure; carotid intima media thickness; hypertension; rheumatoid arthritis
18.  Associations between APOE Genotypes and Disease Susceptibility, Joint Damage and Lipid Levels in Patients with Rheumatoid Arthritis 
PLoS ONE  2013;8(4):e60970.
Apolipoprotein E (APOE) genotypes are associated with cardiovascular disease (CVD) and lipid levels. In rheumatoid arthritis (RA), an association has been found with disease activity. We examined the associations between APOE genotypes and disease susceptibility and markers of disease severity in RA, including radiographic joint damage, inflammatory markers, lipid levels and cardiovascular markers.
A Norwegian cohort of 945 RA patients and 988 controls were genotyped for two APOE polymorphisms. We examined longitudinal associations between APOE genotypes and C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) as well as hand radiographs (van der Heijde Sharp Score(SHS)) in 207 patients with 10 year longitudinal data. Lipid levels, cardiovascular markers and history of CVD were compared across genotypes in a cross sectional study of 136 patients. Longitudinal radiological data of cohorts from Lund and Leiden were available for replication. (N = 935, with 4799 radiographs).
In the Norwegian cohort, associations between APOE genotypes and total cholesterol (TC) and low-density lipoproteins (LDL) were observed (ε2<ε3/ε3<ε4, p = 0.03 and p = 0.02, respectively). No association was present for acute phase reactant or CVD markers, but a longitudinal linear association between APOE genotypes and radiographic joint damage was observed (p = 0.007). No association between APOE genotypes and the severity of joint destruction was observed in the Lund and Leiden cohorts, and a meta- analysis combining all data was negative.
APOE genotypes are associated with lipid levels in patients with RA, and may contribute to dyslipidemia in some patients. APOE genotypes are not consistently associated with markers of inflammation or joint destruction in RA.
PMCID: PMC3629235  PMID: 23613766
19.  Interaction Analysis between HLA-DRB1 Shared Epitope Alleles and MHC Class II Transactivator CIITA Gene with Regard to Risk of Rheumatoid Arthritis 
PLoS ONE  2012;7(3):e32861.
HLA-DRB1 shared epitope (SE) alleles are the strongest genetic determinants for autoantibody positive rheumatoid arthritis (RA). One of the key regulators in expression of HLA class II receptors is MHC class II transactivator (CIITA). A variant of the CIITA gene has been found to associate with inflammatory diseases.
We wanted to explore whether the risk variant rs3087456 in the CIITA gene interacts with the HLA-DRB1 SE alleles regarding the risk of developing RA. We tested this hypothesis in a case-control study with 11767 individuals from four European Caucasian populations (6649 RA cases and 5118 controls).
We found no significant additive interaction for risk alleles among Swedish Caucasians with RA (n = 3869, attributable proportion due to interaction (AP) = 0.2, 95%CI: −0.2–0.5) or when stratifying for anti-citrullinated protein antibodies (ACPA) presence (ACPA positive disease: n = 2945, AP = 0.3, 95%CI: −0.05–0.6, ACPA negative: n = 2268, AP = −0.2, 95%CI: −1.0–0.6). We further found no significant interaction between the main subgroups of SE alleles (DRB1*01, DRB1*04 or DRB1*10) and CIITA. Similar analysis of three independent RA cohorts from British, Dutch and Norwegian populations also indicated an absence of significant interaction between genetic variants in CIITA and SE alleles with regard to RA risk.
Our data suggest that risk from the CIITA locus is independent of the major risk for RA from HLA-DRB1 SE alleles, given that no significant interaction between rs3087456 and SE alleles was observed. Since a biological link between products of these genes is evident, the genetic contribution from CIITA and class II antigens in the autoimmune process may involve additional unidentified factors.
PMCID: PMC3312880  PMID: 22461888
20.  The soluble biomarker calprotectin (a S100 protein) is associated to ultrasonographic synovitis scores and is sensitive to change in patients with rheumatoid arthritis treated with adalimumab 
Arthritis Research & Therapy  2011;13(5):R178.
Calprotectin (MRP8/MRP14, S100A8/A9) is associated with disease activity in patients with rheumatoid arthritis (RA). Ultrasonography (US) is a reliable method for evaluation of synovitis (B-mode (BM) and power Doppler (PD)). The present objectives were to explore in RA patients the associations between calprotectin and a comprehensive US examination, as well as the responsiveness of calprotectin compared to other inflammatory markers during anti-TNF treatment.
A total of 20 RA patients starting treatment with adalimumab were examined longitudinally by US (BM and PD (semi-quantitative scores 0 to 3) of 78 joints, 36 tendons/tendon groups and 2 bursae) and clinically at baseline and after 1, 3, 6 and 12 months. Associations between the US sum scores and the inflammatory markers calprotectin, serum amyloid A (SAA), CRP and ESR were explored by correlation and linear regression analyses, and the response to treatment was assessed by Standardized Response Mean (SRM).
The inflammatory markers, clinical examinations and US sum scores improved during treatment (P < 0.001). Of the inflammatory markers, calprotectin had the highest correlation coefficients with the total BM and PD sum scores (median (range) 0.59 (0.37 to 0.76) for BM and 0.56 (0.38 to 0.72) for PD). Even higher correlations were found between calprotectin and sum US scores of reduced number of joint counts. Calprotectin made a considerable contribution to total US sum scores in the linear regression analyses (P = 0.001 to 0.031) and among the inflammatory markers, calprotectin had the highest SRM (0.84 at one month).
Calprotectin was associated with the sum scores from a comprehensive US assessment and was responsive to change during anti-TNF treatment. Thus, examination of this leukocyte protein could be of additional value in the assessment of RA patients on biologic treatment.
PMCID: PMC3308113  PMID: 22029973
Calprotectin; acute phase proteins; rheumatoid arthritis; ultrasonography; anti-TNF treatment
21.  Comparisons of 7- to 78-joint ultrasonography scores: all different joint combinations show equal response to adalimumab treatment in patients with rheumatoid arthritis 
The primary objectives were to explore the associations between a comprehensive ultrasonographic (US) assessment of joints, tendons and bursae and previously described reduced joint counts (7-, 12-, 28- and 44-joint score) as well as to assess the sensitivity to change of these different US joint combinations during biological treatment.
Twenty patients with rheumatoid arthritis (RA) were examined by US (B-mode (BM) and power Doppler (PD)) with use of a semi-quantitative (0 to 3) score of 78 joints, 36 tendons/tendon groups and two bursae (hereafter described as the 78-joint score) at baseline and 1, 3, 6 and 12 months after initiating treatment with adalimumab. BM and PD scores for the different joint combinations were generated.
The reduced joint scores had high correlation coefficients with the 78-joint score at all examinations (range 0.79 to 0.99 for BM and 0.77 to 0.99 for PD, each P < 0.001) and sum BM and PD scores of all the different joint combinations improved significantly during follow-up (P ≤ 0.05 to 0.001).
The reduced joint combinations were highly associated to the 78-joint score. Furthermore, all the joint combinations presently explored responded well to biological treatment. This indicates that an approach focusing on few joints and tendons gives equivalent information about the inflammatory activity in RA patients as a comprehensive US examination. The optimal combination of joints and tendons for a valid, reliable and feasible US measurement should be further explored to define a US score for follow-up of RA patients on biological treatment.
PMCID: PMC3218888  PMID: 21619619
22.  Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis 
Annals of the Rheumatic Diseases  2011;70(6):909-920.
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.
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.
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.
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.
PMCID: PMC3086093  PMID: 21378402
23.  Adalimumab reduces hand bone loss in rheumatoid arthritis independent of clinical response: Subanalysis of the PREMIER study 
Anti-TNF therapy has been shown to reduce radiographic joint damage in rheumatoid arthritis (RA) independent of clinical response. This has previously not been examined for periarticular bone loss, the other characteristic feature of bone involvement in RA.
The objective of this study was to examine if treatment with the TNF-α inhibitor adalimumab also could reduce periarticular bone loss in RA patients independent of disease activity.
RA patients were recruited from the PREMIER study and included 214 patients treated with methotrexate (MTX) plus adalimumab and 188 patients treated with MTX monotherapy. Periarticular bone loss was assessed by digital X-ray radiogrammetry metacarpal cortical index (DXR-MCI). Change in DXR-MCI was evaluated in patients with different levels of clinical response, as assessed by changes in DAS28 score at 52 weeks and in mean C-reactive protein (CRP) levels during follow-up.
In the MTX group, there was a greater median DXR-MCI loss among patients with moderate and high disease activity compared to those in remission or with low disease activity (-3.3% vs. -2.2%, p = 0.01). In contrast, periarticular bone loss was independent of disease activity (-1.9% vs. -2.4%, p = 0.99) in the combination group. In the MTX group patients with a mean CRP of ≥ 10 mg/l lost significantly more DXR-MCI than patients with low CRP (-3.1% vs. -1.9%, p <0.01) whereas in the combination group no significant differences between the two CRP groups was seen (-2.4% vs. -2.0%, p = 0.48).
Adalimumab in combination with MTX reduces periarticular bone loss independently of clinical response. These results support the hypothesis that TNF-α stimulates the osteoclast not only by the inflammatory pathway but do also have a direct effect on the osteoclast.
Trial Registration
ClinicalTrials (NCT): NCT001195663
PMCID: PMC3053306  PMID: 21352592
24.  Anti-PAD4 autoantibodies in rheumatoid arthritis: levels in serum over time and impact on PAD4 activity as measured with a small synthetic substrate 
Rheumatology International  2011;32(5):1271-1276.
Isoform 4 of the human peptidylarginine deiminase (hPAD4) enzyme may be responsible for the citrullination of antigens in rheumatoid arthritis (RA) and has been shown to be itself the target of disease-specific autoantibodies. Here, we have tested whether the level of serum anti-hPAD4 antibodies in RA patients is stable over a period of 10 years and whether the antibodies influence hPAD4-mediated deimination of the small substrate N-α-Benzoyl-l-arginine ethyl ester. RA sera (n = 128) obtained at baseline and after 10 years were assessed for anti-hPAD4 antibodies by a specific immunoassay. For 118 RA patients, serum anti-hPAD4 IgG levels were stable over 10 years. Seven patients who were negative for anti-PAD4 IgG at baseline had become positive after 10 years. Further, total IgG from selected RA patients and controls were purified, and a fraction was depleted for anti-hPAD4 antibodies. Kinetic deimination assays were performed with total IgG and depleted fractions. The kcat and Km values of hPAD4-mediated deimination of N-α-Benzoyl-l-arginine ethyl ester were not affected by the depletion of the anti-hPAD4 antibodies from the total IgG pool. In conclusion, RA patients remain positive for anti-hPAD4 antibodies over time and some patients who are initially anti-hPAD4 negative become positive later in the disease course. The anti-hPAD4 antibodies did not affect the enzymatic activity of hPAD4 when the small substrate N-α-Benzoyl-l-arginine ethyl ester was used. However, this finding may not exclude an effect of these autoantibodies on citrullination of protein substrates in RA.
PMCID: PMC3336063  PMID: 21267570
Rheumatoid arthritis; Peptidylarginine deiminase 4; Citrulline; Autoantibodies; Medicine & Public Health; Rheumatology
25.  A CLEC16A variant confers risk for juvenile idiopathic arthritis and anti-cyclic citrullinated peptide antibody negative rheumatoid arthritis 
Annals of the Rheumatic Diseases  2010;69(8):1471-1474.
Variants in CLEC16A have conferred susceptibility to autoimmune diseases in genome-wide association studies. The present work aimed to investigate the locus' involvements in juvenile idiopathic arthritis (JIA) and further explore the association with rheumatoid arthritis (RA), type 1 diabetes (T1D) and Addison's disease (AD) in the Norwegian population.
Three single nucleotide polymorphisms (SNPs) were genotyped in patients with RA (n=809), JIA (n=509), T1D (n=1211) and AD (n=414) and in healthy controls (n=2149).
All diseases were associated with CLEC16A, but with different SNPs. The intron 22 SNP, rs6498169, was associated with RA (p=0.006) and JIA (p=0.016) and the intron 19 SNPs, rs12708716/rs12917716, with T1D (p=1×10−5) and AD (p=2×10−4). The RA association was confined to the anti-cyclic citrullinated peptide antibody (anti-CCP) negative subgroup (p=2×10−4).
This is the first report of a CLEC16A association with JIA and a split of the RA association according to anti-CCP status. Different causative variants underlie the rheumatic versus the organ specific diseases.
PMCID: PMC2938883  PMID: 19734133

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