Rheumatoid Arthritis: Jacobsen S

Larsen C, Ostergaard J, Larsen SW, Jensen H, Jacobsen S, Lindegaard C, Andersen PH. · Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark. · J Pharm Sci. · Pubmed #18306275 No free full text.

Abstract: The joint cavity constitutes a discrete anatomical compartment that allows for local drug action after intra-articular injection. Drug delivery systems providing local prolonged drug action are warranted in the management of postoperative pain and not least arthritic disorders such as osteoarthritis. The present review surveys various themes related to the accomplishment of the correct timing of the events leading to optimal drug action in the joint space over a desired time period. This includes a brief account on (patho)physiological conditions and novel potential drug targets (and their location within the synovial space). Particular emphasis is paid to (i) the potential feasibility of various depot formulation principles for the intra-articular route of administration including their manufacture, drug release characteristics and in vivo fate, and (ii) how release, mass transfer and equilibrium processes may affect the intra-articular residence time and concentration of the active species at the ultimate receptor site.

Troelsen LN, Jacobsen S. · H:S Rigshospitalet, Finsencentret, Reumatologisk Klinik 4242, København Ø. · Ugeskr Laeger. · Pubmed #17032593 No free full text.

Abstract: Rheumatoid arthritis is associated with increased cardiovascular morbidity and mortality due to atherosclerosis. This cannot be explained by an increased presence of traditional risk factors but seems to depend on inflammatory mechanisms. The association of inflammatory pathways with atherosclerosis is complex, and more research is required to optimise preventative measures against cardiovascular complications in inflammatory rheumatic diseases.

Jacobsen S. · H:S Hvidovre Hospital, reumatologisk klinik. · Ugeskr Laeger. · Pubmed #10689949 No free full text.

Abstract: OBJECTIVES: To determine whether short-term (i.e. as recorded within the first month of therapy), oral low-dose corticosteroids (corresponding to a maximum of 15 mg prednisolone daily) is superior to placebo and nonsteroidal, antiinflammatory drugs in patients with rheumatoid arthritis. SEARCH STRATEGY: Medline Silverplatter, The Cochrane Controlled Trials Register, reference lists and a personal archive. SELECTION CRITERIA: All randomised studies comparing an oral corticosteroid (not exceeding an equivalent of 15 mg prednisolone daily) with placebo or a nonsteroidal, antiinflammatory drug were eligible if they reported clinical outcomes within one month after start of therapy. DATA COLLECTION AND ANALYSIS: Decisions on which trials to include were made independently by two observers based on the methods sections of the trials only. Standardised effect measures were used for the statistical analyses; the random effects model was used if p < 0.10 for the test of heterogeneity. MAIN RESULTS: Ten studies, involving 320 patients, were included in the meta-analysis. Prednisolone had a marked effect over placebo on joint tenderness (standardised effect size 1.31, 95% confidence interval 0.78 to 1.83), pain (standardised effect size 1.75, 0.87 to 2.64) and grip strength (standardised effect size 0.41, 0.13 to 0.69). Measured in the original units, the differences were 12 tender joints (6 to 18) and 22 mmHg (5 to 40) for grip strength. Prednisolone also had a greater effect than nonsteroidal, antiinflammatory drugs on joint tenderness (standardised effect size 0.63, 0.11 to 1.16) and pain (standardised effect size 1.25, 0.26 to 2.24), whereas the difference in grip strength was not significant (standardised effect size 0.31, -0.02 to 0.64). Measured in the original units, the differences were 9 tender joints (5 to 12) and 12 mmHg (-6 to 31). The risk of adverse effects, also during moderate- and long-term use, seemed acceptable. CONCLUSIONS: Prednisolone in low doses (not exceeding 15 mg daily) may be used intermittently in patients with rheumatoid arthritis, particularly if the disease cannot be controlled by other means. Since prednisolone is highly effective, short-term placebo controlled trials studying the clinical effect of low-dose prednisolone or other oral corticosteroids are no longer necessary.

Jacobsen S, Garred P, Madsen HO, Heegaard NH, Hetland ML, Stengaard-Pedersen K, Junker P, Lottenburger T, Ellingsen T, Smedegaard Andersen L, Hansen I, Skjødt H, Pedersen JK, Lauridsen UB, Svendsen AJ, Tarp U, Pødenphant J, Lindegaard H, Vestergaard A, Østergaard M, Hørslev-Petersen K. · Department of Rheumatology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. · J Rheumatol. · Pubmed #19273450 No free full text.

Abstract: OBJECTIVE: To study the association between polymorphisms in the mannose-binding lectin gene (MBL2) and disease activity, physical disability, and joint erosions in patients with newly diagnosed rheumatoid arthritis (RA). METHODS: Patients with early RA (n=158) not previously treated with disease modifying antirheumatic drugs, participating in a treatment trial (CIMESTRA study) were examined at inclusion for MBL2 pooled structural genotypes (O/O, A/O, A/A), regulatory MBL2 promoter polymorphism in position -221 (XX, XY, YY), anti-cyclic citrullinated peptide 2 antibodies (anti-CCP2), disease activity by Disease Activity Score-28 (DAS28 score), physical disability by Health Assessment Questionnaire (HAQ) score, and erosive changes in hands and feet (Sharp-van der Heijde score). RESULTS: Eight patients were homozygous MBL2 defective (O/O), 101 belonged to an intermediate group, and 49 were MBL2 high producers (YA/YA). Anti-CCP was present in 93 patients (59%). High scores of disease activity, C-reactive protein-based DAS28 (p=0.02), and physical disability by HAQ (p=0.01) were associated with high MBL2 expression genotypes in a gene-dose dependent way, but only in anti-CCP-positive patients. At this early stage of the disease there was no association with erosion score from radiographs. CONCLUSION: The results point to a synovitis-enhancing effect of MBL in anti-CCP-positive RA, whereas such an effect was not demonstrated for joint erosions.

Sennels H, Sørensen S, Ostergaard M, Knudsen L, Hansen M, Skjødt H, Peters N, Colic A, Grau K, Jacobsen S. · Department of Clinical Biochemistry, Hvidovre Hospital, Copenhagen University Hospital, Hvidovre, Denmark. · Scand J Rheumatol. · Pubmed #18612923 No free full text.

Abstract: OBJECTIVE: To determine whether circulating levels of osteopontin (OPN), osteoprotegerin (OPG), total soluble receptor activator of nuclear factor-kappa B ligand (total sRANKL), and high-sensitivity C-reactive protein (hsCRP) change in patients with rheumatoid arthritis (RA) during immunosuppressive therapy. METHODS: Twenty-five active RA patients were randomized to treatment with either etanercept alone or in combination with methotrexate (MTX). The treatment response after 16 weeks was assessed using the European League Against Rheumatism (EULAR) response criteria. Blood samples were taken before the start of and every fourth week during the study. OPN, OPG, and total sRANKL were measured by enzyme-linked immunosorbent assays (ELISAs) and hsCRP by highly sensitive turbidometry. RESULTS: At baseline, OPN and hsCRP were significantly (p<0.001) elevated compared to healthy persons. Compared to baseline only hsCRP levels decreased significantly (p<0.05 to p<0.001) in the EULAR responders through the study. OPN remained significantly (p<0.05) elevated at 16 weeks in patients with a low disease activity score (DAS< or =3.2). Total sRANKL increased significantly (p<0.05) from baseline to week 12. No statistically significant changes were observed in the non-responders. CONCLUSION: Active RA patients showed increased circulating levels of hsCRP and OPN, but only hsCRP decreased during etanercept therapy. Our findings suggest that OPN, OPG, total sRANKL, and hsCRP reflect different aspects of the inflammatory process in RA.

Källberg H, Jacobsen S, Bengtsson C, Pedersen M, Padyukov L, Garred P, Frisch M, Karlson EW, Klareskog L, Alfredsson L. · Institute of Environmental Medicine, Box 210, Karolinska Institutet, 17177 Stockholm, Sweden. · Ann Rheum Dis. · Pubmed #18535114 No free full text.

Abstract: OBJECTIVES: To determine the association between risk of rheumatoid arthritis (RA) and alcohol consumption in combination with smoking and HLA-DRB1 shared epitope (SE). METHODS: Data from two independent case-control studies of RA, the Swedish EIRA (1204 cases and 871 controls) and the Danish CACORA (444 cases and 533 controls), were used to estimate ORs of developing RA for different amounts of alcohol consumed. RESULTS: Alcohol consumption was significantly more common in controls (p<0.05) and dose-dependently associated with reduced risk of RA (p for trend <0.001) in both studies. Among alcohol consumers, the quarter with the highest consumption had a decreased risk of RA of the order of 40-50% compared with the half with the lowest consumption (EIRA, OR = 0.5 (95% CI 0.4 to 0.6); CACORA, OR = 0.6 (95% CI 0.4 to 0.9)). For the subset of RA that is seropositive for antibodies to citrullinated peptide antigens, alcohol consumption reduced the risk most in smokers carrying HLA-DRB1 SE alleles. CONCLUSIONS: The observed inverse association between alcohol intake and risk of RA and the recent demonstration of a preventive effect of alcohol in experimental arthritis indicate that alcohol may protect against RA. This highlights the potential role of lifestyle in determining the risk of developing RA, and emphasises the advice to stop smoking, but not necessarily to abstain from alcohol in order to diminish risk of RA. The evidence of potential RA prevention should prompt additional studies on how this can be achieved.

Broholm B, Ullman S, Halberg P, Jacobsen S. · Department of Rheumatology, 4242, Rigshospitalet, University Hospital of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark. · Clin Rheumatol. · Pubmed #18528725 No free full text.

Abstract: Smoking is a known risk factor for the development of several lung diseases, autoimmune diseases, and IgM rheumatoid factor (RF) in nonrheumatic persons. In patients with rheumatoid arthritis and IgM RF the diffusion capacity is decreased in smokers but not in nonsmokers. In the present study of patients with systemic sclerosis (SSc) the influence of smoking and IgM RF on the lung function was calculated. One hundred fifty-five persons with SSc had vital capacity (VC) and diffusing capacity (DLco) measured at least twice with at least 1-year interval as percents of predicted values according to gender, age, height, and weight. The yearly changes in VC and DLco were calculated, Delta VC and Delta DLco, respectively. IgM RF was measured at the beginning of the study. Smoking was defined as having ever smoked. Statistically significant deterioration of VC and DLco in patients with circulating IgM RF was found only in smokers or previous smokers, P = 0.007 and P = 0.01, respectively. These findings were confirmed by means of multiple regression analyses. The presence of IgM RF in smoking SSc patients is associated with deteriorating lung function. Whether this is a causal association and whether the presence of IgM RF in smoking patients with SSc actually confers an increased risk of pulmonary damage remains to be determined.

Hetland ML, Ejbjerg B, Hørslev-Petersen K, Jacobsen S, Vestergaard A, Jurik AG, Stengaard-Pedersen K, Junker P, Lottenburger T, Hansen I, Andersen LS, Tarp U, Skjødt H, Pedersen JK, Majgaard O, Svendsen AJ, Ellingsen T, Lindegaard H, Christensen AF, Vallø J, Torfing T, Narvestad E, Thomsen HS, Ostergaard M, Anonymous00063. · Department of Rheumatology, Copenhagen University Hospital, Hvidovre, Denmark. · Ann Rheum Dis. · Pubmed #18388160 No free full text.

Abstract: OBJECTIVE: To identify predictors of radiographic progression in a 2-year randomised, double-blind, clinical study (CIMESTRA) of patients with early rheumatoid arthritis (RA). METHODS: Patients with early RA (n = 130) were treated with methotrexate, intra-articular betamethasone and ciclosporin/placebo-ciclosporin. Baseline magnetic resonance imaging (MRI) of the wrist (wrist-only group, n = 130) or MRI of wrist and metacarpophalangeal (MCP) joints (wrist+MCP group, n = 89) (OMERACT RAMRIS), x-ray examination of hands, wrists and forefeet (Sharp/van der Heijde Score (TSS)), Disease Activity Score (DAS28), anti-cyclic citrullinated peptide antibodies (anti-CCP), HLA-DRB1-shared epitope (SE) and smoking status were assessed. Multiple regression analysis was performed with delta-TSS (0-2 years) as dependent variable and baseline DAS28, TSS, MRI bone oedema score, MRI synovitis score, MRI erosion score, anti-CCP, smoking, SE, age and gender as explanatory variables. RESULTS: Baseline values: median DAS28 5.6 (range 2.4-8.0); anti-CCP positive 61%; radiographic erosions 56%. At 2 years: DAS28 2.0 (0.5-5.7), in DAS remission: 56%, radiographic progression 26% (wrist+MCP group, similar for wrist-only group). MRI bone oedema score was the only independent predictor of delta-TSS (wrist+MCP group: coefficient = 0.75 (95% CI 0.55 to 0.94), p<0.001; wrist-only group: coefficient = 0.59 (95% CI 0.40 to 0.77), p<0.001). Bone oedema score explained 41% of the variation in the progression of TSS (wrist+MCP group), 25% in wrist-only group (Pearson's r = 0.64 and r = 0.50, respectively). Results were confirmed by sensitivity analyses. CONCLUSION: In a randomised controlled trial aiming at remission in patients with early RA, baseline RAMRIS MRI bone oedema score of MCP and wrist joints (and of wrist only) was the strongest independent predictor of radiographic progression in hands, wrists and forefeet after 2 years. MRI synovitis score, MRI erosion score, DAS28, anti-CCP, SE, smoking, age and gender were not independent risk factors. TRIAL REGISTRATION NUMBER: NCT00209859.

Holm B, Jacobsen S, Skjodt H, Klarlund M, Jensen T, Hetland ML, Ostergaard M. · Department of Physiotherapy, Copenhagen University Hospital at Hvidovre, Copenhagen, Denmark. · Phys Ther. · Pubmed #18276936 links to  free full text

Abstract: BACKGROUND AND PURPOSE: The purpose of this study was to translate the German Keitel Functional Test (KFT) into Danish and test it for reliability, concurrent and predictive validity, and responsiveness in patients with rheumatoid arthritis (RA). METHODS: Translation of the KFT was performed according to international recommendations, and the translated version was tested twice by 2 observers for intraobserver and interobserver reliability, with a 1-week interval between assessments, in 20 patients with RA with stable disease activity. Validity was investigated by studying 2 patient groups: (1) 15 patients with long-lasting (median=6 years) active RA, tested before and after 2, 6, and 14 weeks of anti-tumor necrosis factor alpha (TNF-alpha) inhibitor therapy, and (2) 35 patients with early (median=0.25 year) RA, tested at years 0, 0.5, 1, and 2. Twenty-three patients in the early RA group also were tested at year 7. KFT, conventional clinical and biochemical markers of disease activity, and Health Assessment Questionnaire (HAQ) were used. RESULTS: The translated KFT showed good intraobserver reliability (intraclass correlation coefficients [ICC]=.90 and .95, coefficient of variation [CV]=3.5%) and interobserver reliability (ICC=.99 and .92, CV=3.5%), and the KFT correlated with several measures of disease activity and, most closely, with the HAQ. The KFT was, in contrast to clinical disease activity measures, not sensitive to changes over time. Only baseline KFT data were significantly related to functional changes over a long period of time as measured by the KFT, and only in the early RA group. DISCUSSION AND CONCLUSION: The Danish translation of the KFT showed good reliability, acceptable concurrent validity, very poor responsiveness, and inconclusive results concerning predictive validity. The results of this study do not support the use of the KFT for monitoring function in clinical practice, as an outcome measure in clinical trials, or as a predictor of functional changes.

Pedersen M, Jacobsen S, Garred P, Madsen HO, Klarlund M, Svejgaard A, Pedersen BV, Wohlfahrt J, Frisch M. · Danish Epidemiology Science Centre, Statens Serum Institut, Copenhagen, Denmark. · Arthritis Rheum. · Pubmed #17469102 links to  free full text

Abstract: OBJECTIVE: To study the role of shared epitope (SE) susceptibility genes, alone and in combination with tobacco smoking and other environmental risk factors, for risk of subtypes of rheumatoid arthritis (RA) defined by the presence or absence of serum antibodies against cyclic citrullinated peptides (CCPs). METHODS: To address these issues, a nationwide case-control study was conducted in Denmark during 2002-2004, comprising incident cases of RA or patients with recently diagnosed RA (309 seropositive and 136 seronegative for IgG antibodies against CCP) and 533 sex- and age-matched population controls. Associations were evaluated by logistic regression analyses, in which odds ratios (ORs) served as measures of relative risk. RESULTS: Compared with individuals without SE susceptibility genes, SE homozygotes had an elevated risk of anti-CCP-positive RA (OR 17.8, 95% confidence interval [95% CI] 10.8-29.4) but not anti-CCP-negative RA (OR 1.07, 95% CI 0.53-2.18). Strong combined gene-environment effects were observed, with markedly increased risks of anti-CCP-positive RA in SE homozygotes who were heavy smokers (OR 52.6, 95% CI 18.0-154), heavy coffee drinkers (OR 53.3, 95% CI 15.5-183), or oral contraceptive users (OR 44.6, 95% CI 15.2-131) compared with SE noncarriers who were not exposed to these environmental risk factors. CONCLUSION: Persons who are homozygous for SE susceptibility genes, notably those who are also exposed to environmental risk factors, have a markedly and selectively increased risk of anti-CCP-positive RA. A distinction between anti-CCP-positive RA and anti-CCP-negative RA seems warranted, because these RA subtypes most likely represent etiologically distinct disease entities.

Troelsen LN, Garred P, Madsen HO, Jacobsen S. · Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. · Arthritis Rheum. · Pubmed #17195187 links to  free full text

Abstract: OBJECTIVE: Patients with rheumatoid arthritis (RA) have excess morbidity and mortality due to ischemic heart disease. It has been suggested that high serum levels of mannose-binding lectin (MBL) and agalactosyl IgG (IgG-G0) are associated with increased inflammation in RA. MBL also enhances inflammation-mediated tissue injury during postischemic reperfusion. This study was undertaken to examine whether these factors are associated with increased risk of ischemic heart disease in RA. METHODS: MBL alleles were genotyped in 229 Danish patients with RA. In addition, serum levels of MBL and IgG-G0 were measured. Incidences of ischemic heart disease, myocardial infarction, and death due to ischemic heart disease after the diagnosis of RA were assessed in a prospective study. RESULTS: During a median followup of 9.5 years, ischemic heart disease was diagnosed in 8 of 27 patients with genetically determined high serum levels of MBL, as compared with 24 of the remaining 192 patients (data not available on 10 patients). After correction for other known risk factors, the hazard ratio (HR) was 3.6 (95% confidence interval [95% CI] 1.4-9.2). The corrected HR for myocardial infarction was 9.0 (95% CI 2.2-36.4). High serum levels of MBL also conferred an increased risk of death due to ischemic heart disease (age- and sex-adjusted HR 10.5, 95% CI 2.7-41.3). However, further analyses showed that these associations were present only in patients with high serum levels of IgG-G0. CONCLUSION: Genetically determined high serum levels of MBL and high serum levels of IgG-G0 are associated with increased risk of ischemic heart disease, myocardial infarction, and premature death in patients with RA.

Pedersen M, Jacobsen S, Klarlund M, Pedersen BV, Wiik A, Wohlfahrt J, Frisch M. · Department of Epidemiology Research, Danish Epidemiology Science Centre, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark. · Arthritis Res Ther. · Pubmed #16872514 links to  free full text

Abstract: The aim of this study was to evaluate new and previously hypothesised non-genetic risk factors for serologic subtypes of rheumatoid arthritis (RA) defined by the presence or absence of auto-antibodies to cyclic citrullinated peptides (CCP). In a national case-control study, we included 515 patients recently diagnosed with RA according to the American College of Rheumatology 1987 classification criteria and 769 gender- and age-matched population controls. Telephone interviews provided information about non-genetic exposures, and serum samples for patients were tested for anti-CCP-antibodies. Associations between exposure variables and risk of anti-CCP-positive and anti-CCP-negative RA were evaluated using logistic regression. A series of RA subtype-specific risk factors were identified. Tobacco smoking (odds ratio [OR] = 1.65; 95% confidence interval: 1.03-2.64, for > 20 versus 0 pack-years) was selectively associated with risk of anti-CCP-positive RA, whereas alcohol consumption exhibited an inverse dose-response association with this RA subtype (OR = 1.98, 1.22-3.19, for 0 versus > 0-5 drinks per week). Furthermore, coffee consumption (OR = 2.18; 1.07-4.42, for > 10 versus 0 cups per day), ever use of oral contraceptives (OR = 1.65; 1.06-2.57) and having a first-degree relative with schizophrenia (OR = 4.18; 1.54-11.3) appeared more strongly associated with risk of anti-CCP-positive RA. Obesity was selectively associated with risk of anti-CCP-negative RA, with obese individuals being at more than 3-fold increased risk of this subtype compared with normal-weight individuals (OR = 3.45; 1.73-6.87). Age at menarche was the only examined factor that was significantly associated with both serologic subtypes of RA (p-trends = 0.01); women with menarche at age > or = 15 years had about twice the risk of either RA subtype compared with women with menarche at age < or = 12 years. Major differences in risk factor profiles suggest distinct etiologies for anti-CCP-positive and anti-CCP-negative RA.

Pedersen M, Jacobsen S, Klarlund M, Frisch M. · Department of Epidemiology Research, Danish Epidemiology Science Centre, Statens Serum Insitut, DK-2300 København S, Denmark. · J Rheumatol. · Pubmed #16622905 No free full text.

Abstract: OBJECTIVE: To examine whether markers of socioeconomic status (SES) are associated with risk of rheumatoid arthritis (RA), and if so, whether selected lifestyle-related factors could explain this association. METHODS: We conducted a frequency matched case-control study; subjects comprised 515 patients (participation rate 83%) attending rheumatology and internal medicine departments in Denmark, with recently diagnosed RA according to the American College of Rheumatology (ACR) 1987 classification criteria for RA (mean disease duration 2.3 yrs), and 769 frequency-matched population controls (participation rate 64%). Information about SES and environmental exposure was obtained by structured telephone interview. Logistic regression analyses evaluated the role of markers of SES. RESULTS: Level of education was significantly inversely associated with risk of RA, with a 2-fold lower risk of RA among those with the longest formal education compared with those having the lowest level of education (multivariate odds ratio = 0.43, 95% confidence interval 0.24-0.76, p trend = 0.001). None of a series of studied lifestyle factors could explain this finding in multivariate logistic regression analyses. When dividing the RA cases into clinical subgroups, the inverse association with level of education was found to apply predominantly to rheumatoid factor (RF)-positive RA. CONCLUSION: The inverse association between level of education and risk of RF-positive RA was not explained by any of the examined lifestyle factors. RF-positive and RF-negative RA may be 2 distinct diseases with different etiologies, with unmeasured factors related to educational level predominantly associated with the risk of RF-positive RA. However, because mechanisms underlying referral to a hospital might be linked to educational level, our observation based on hospital-referred RA patients should be evaluated cautiously. The study stresses the importance of taking SES measures into account in studies that aim at identifying environmental risk factors for RA.

Sonne-Holm S, Jacobsen S. · Department of Orthopaedic Surgery and Radiology, Hvidovre University Hospital of Copenhagen, Denmark. · Osteoarthritis Cartilage. · Pubmed #16545585 No free full text.

Abstract: BACKGROUND: The radiological and epidemiological data from the Copenhagen Osteoarthritis Study (COS) were analysed in order to assess the prevalence of osteoarthritis (OA) of the first carpometacarpal joint (CMCJ). Another aim of the study was to analyse relationships between radiologic CMCJ OA and self-reported pain. The third aim was to analyse if additional information could be obtained applying a new method of correlating individual radiological features to self-reported pain, compared to Kellgren and Lawrence's (K-L's) radiologic OA classification. METHODS: Between 1992 and 1994 standardised radiographs of both hands were recorded in 3,355 participants of the COS cohort. Subjects with known rheumatoid arthritis, other inflammatory arthritis or earlier fractures of the hand were excluded. OA of the CMCJ was assessed according to K-L's radiologic classification by two senior radiologists at our institution. The radiologists further evaluated individual radiologic features of CMCJ OA as recommended by K-L according to the text attached to each picture in their radiologic atlas of OA. To estimate inter- and intraobserver reproducibility a subset of 100 radiographs was reread. RESULTS: Our analyses demonstrated that the K-L method was not able to classify all X-rays. In 608 (18.1%) cases, combinations of joint space width (JSW) measurements, the graduation of osteofytes, sclerosis and cysts fell outside the classification. The radiological evaluation of individual features of OA demonstrated an acceptable reproducibility, intrapersonal (kappa=0.79) as well as interpersonal (kappa=0.65). The prevalence of each radiological feature increased after the fifth decade, progressively more so among women (P<0.001), with the highest prevalence (36.0%) of grades 3 and 4 JSW reduction among women>80 years. A significant correlation was found between signs of radiologic degeneration and self-reported pain (P<0.001); however, different combinations of OA features had different relations to symptoms. Logistic regression analyses revealed sclerosis to have an independent influence on pain in the thumb compared with the presence of osteofytes, cysts and diminished JSW. Body mass index (BMI) was positively related to radiological changes. In logistic regression analyses BMI did not demonstrate an independent positive relation to OA. CONCLUSION: Radiological degenerative changes in the CMCJ by age especially among women are quite common. However, it is demonstrated that global radiologic classifications of OA of the CMCJ have serious limitations in epidemiological studies. Not all cases fit into classification based on the K-L-atlas. Among the radiological features, subchondral sclerosis is significantly related to self-reported pain. Specific radiologic data should be incorporated in epidemiological studies on hand OA.

Ejbjerg BJ, Vestergaard A, Jacobsen S, Thomsen H, Østergaard M. · Department of Rheumatology, Copenhagen University Hospitals at Hvidovre and Gentofte, Kettegaard Allé30, 2650 Hvidovre, Denmark. · Arthritis Res Ther. · Pubmed #16542505 links to  free full text

Abstract: The aim of this study was to demonstrate the ability of conventional radiography to detect bone erosions of different sizes in metacarpophalangeal (MCP) joints of rheumatoid arthritis (RA) patients using magnetic resonance imaging (MRI) as the standard reference. A 0.2 T Esaote dedicated extremity MRI unit was used to obtain axial and coronal T1-weighted gradient echo images of the dominant 2nd to 5th MCP joints of 69 RA patients. MR images were obtained and evaluated for bone erosions according to the OMERACT recommendations. Conventional radiographs of the 2nd to 5th MCP joints were obtained in posterior-anterior projection and evaluated for bone erosions. The MRI and radiography readers were blinded to each other's assessments. Grade 1 MRI erosions (1% to 10% of bone volume eroded) were detected by radiography in 20%, 4%, 7% and 13% in the 2nd, 3rd, 4th and 5th MCP joint, respectively. Corresponding results for grade 2 erosions (11% to 20% of bone volume eroded) were 42%, 10%, 60% and 24%, and for grade 3 erosions (21% to 30% of bone volume eroded) 75%, 67%, 75% and 100%. All grade 4 (and above) erosions were detected on radiographs. Conventional radiography required a MRI-estimated bone erosion volume of 20% to 30% to allow a certain detection, indicating that MRI is a better method for detection and grading of minor erosive changes in RA MCP joints.

Jensen CH, Jacobsen S, Ratchke M, Sonne-Holm S. · Department of Orthopaedics, Copenhagen University Hospital of Hvidovre, Denmark. · Acta Orthop. · Pubmed #16534715 links to  free full text

Abstract: BACKGROUND: The optimal design of an elbow prosthesis for badly damaged elbows is unkown. We evaluated 23 GSB III semi-constrained (sloppy-hinged) total elbow arthroplasties in 16 consecutive patients with rheumatoid arthritis. PATIENTS AND METHODS: After a mean follow-up period of 5 (2-9) years, we assessed quality of the cementing technique, signs of aseptic loosening, patient satisfaction, range of movement, and determined the Hospital for Special Surgery (HSS) elbow score. 3 patients had died before follow-up; thus, 20 replacements in 16 patients were available for clinical and radiographic study. All patients had endstage rheumatoid arthritis (RA) of the elbow joint. RESULTS: In 2 patients, humeral components were revised due to malorientation. 1 arthroplasty was revised due to aseptic loosening of the humeral component. There were 4 cases of intraoperative fracture which healed uneventfully. The total rate of complications was thus one-third. In 17 of 40 components, the cementing technique was rated as marginal or inadequate. We found no association between cementing technique and loosening. The arc of extension/flexion increased by 19 degrees (0-80), and the range of pronation/supination increased by 31 degrees (0-130). There were no cases of infection or ulnar nerve dysfunction. At the latest follow-up, the HSS elbow score was 84 (40-100) points. 11 of 20 elbows were rated as excellent, 4 elbows were rated as good, 2 elbows were rated as fair, and 3 elbows were rated as poor. 14 of 16 patients were satisfied with the result and the 2 patients who were not satisfied had persistent pain. INTERPRETATION: Despite the inherent problems of cementing in small-calibre medullary cavities, the clinical outcome of the GSB III arthroplasty was encouraging for patients with-end stage RA. The rate of overall complications compared favorably with other studies of semiconstrained elbow arthroplasty for end-stage RA. Most complications of the series were minor and did not necessitate revision.

Ejbjerg BJ, Vestergaard A, Jacobsen S, Thomsen HS, Østergaard M. · Copenhagen University Hospitals at Hvidovre, Rigshospitalet, and Herlev, Denmark. · Arthritis Rheum. · Pubmed #16052593 links to  free full text

Abstract: OBJECTIVE: To compare 2 magnetic resonance imaging (MRI) approaches and radiographic evaluation according to the Sharp/van der Heijde method with respect to sensitivity to change in joint destruction in patients with rheumatoid arthritis (RA). METHODS: Thirty-five RA patients and 9 healthy controls underwent MRI and radiography on 2 occasions 1 year apart. Conventional radiographs of the hands, wrists, and forefeet were evaluated according to the Sharp/van der Heijde method. MRIs of unilateral wrist and second through fifth metacarpophalangeal (MCP) joints ("few-joints approach") and of bilateral wrist and MCP joints plus unilateral metatarsophalangeal (MTP) joints ("many-joints approach") were assessed for bone erosions according to the scoring system recommended by the OMERACT (Outcome Measures in Rheumatology Clinical Trials) group. The smallest detectable differences (SDDs) of the radiography and MRI scores were computed based on reevaluation of one-third of the study population. RESULTS: Progressive joint destruction, i.e., an increase in score after the followup period, was observed more frequently with the MRI "many-joints approach" (30 subjects) and "few-joints approach" (25 subjects) than with the Sharp/van der Heijde radiographic method (9 subjects) (P < 0.001 by chi-square analysis). No significant difference between the MRI approaches was observed. When only subjects with a change greater than the SDD were considered, progression was revealed with the MRI "many-joints approach," the MRI "few-joints approach," and radiography in 15, 13, and 5 RA subjects, respectively. With both MRI approaches, significantly more subjects with progression were detected than were detected by radiography (P < 0.05). CONCLUSION: MRI, regardless of whether it covers unilateral wrist and MCP joints or bilateral wrist and MCP joints plus unilateral MTP joints, is significantly superior to radiography of the hands, wrists, and forefeet with respect to detection of progressive joint destruction in RA.

Pedersen M, Klarlund M, Jacobsen S, Svendsen AJ, Frisch M. · Department of Epidemiology Research, Danish Epidemiology Science Centre, Statens Serum Institut, Copenhagen, Denmark. · Eur J Epidemiol. · Pubmed #15678789 No free full text.

Abstract: Discharge diagnoses following hospital admissions in Denmark are recorded in the Danish National Patient Registry (NPR). Such routine hospitalization records may serve as useful research tools in epidemiological studies. The aim of the study was to provide measures of the validity and completeness of rheumatoid arthritis (RA) diagnoses recorded in the NPR. We identified medical records for 217 patients recorded as having RA in the NPR between 1977 and 2001. Using two definitions of RA (clinically confirmed RA and fulfilment of the American College of Rheumatology (ACR) 1987 diagnostic criteria for RA), a rheumatologist assessed the proportion of RA diagnoses recorded in the NPR that could be confirmed by scrutiny of the original medical records. The completeness of RA diagnoses in the NPR was estimated by a two-sample capture-recapture method. Overall, 59% of the 217 RA diagnoses in the NPR were confirmed by information in the medical records. However, major differences were seen according to characteristics of the underlying hospital registrations. Generally, RA diagnoses were most often confirmed for patients registered as inpatients and for patients with more than one hospital registration with RA. Specifically, only 42% of patients with one RA registration from a rheumatology department were confirmed as having RA. In contrast, 91% of patients treated at a rheumatology department and having three or more hospital registrations with RA were confirmed as having RA. The completeness of the NPR with respect to RA satisfying the ACR 1987 classification criteria was estimated to 26%. Our conclusion is that with careful attention to the limitations in the data, discharge diagnoses for patients with records of RA in the Danish NPR can be used for epidemiological research purposes; however, our findings prompt general carefulness when using non-audited registries for research in RA.

Ejbjerg BJ, Narvestad E, Jacobsen S, Thomsen HS, Østergaard M. · Department of Rheumatology, Copenhagen University Hospital at Hvidovre, Kettegaard Allé 30, 2650 Hvidovre, Denmark. · Ann Rheum Dis. · Pubmed #15650012 links to  free full text

Abstract: OBJECTIVE: To evaluate a low field dedicated extremity MRI unit for detection of bone erosions, synovitis, and bone marrow oedema in wrist and metacarpophalangeal (MCP) joints, with a high field MRI unit as the standard reference. METHODS: In 37 patients with RA and 28 healthy controls MRI of the wrist and 2nd-5th MCP joints was performed on a low field MRI unit (0.2 T Esaote Artoscan) and a high field MRI unit (1.0 T Siemens Impact) on 2 subsequent days. MRI was performed and evaluated according to OMERACT recommendations. Additionally, conventional x ray, clinical, and biochemical examinations were performed. In an initial low field MRI "sequence selection phase", based on a subset of 10 patients and 10 controls, sequences for comparison with high field MRI were selected. RESULTS: With high field, spin echo MRI considered as the reference method, the sensitivity, specificity, and accuracy of low field 3D gradient echo MRI for erosions were 94%, 93%, 94%, while the corresponding values for x ray examination were 33%, 98%, and 83%. Sensitivity, specificity, and accuracy of low field MRI for synovitis were 90%, 96%, and 94%, and for bone marrow oedema 39%, 99%, and 95%. Intraclass correlation coefficients between low field and high field scores were 0.936 (p<0.005) for bone erosions and 0.923 (p<0.05) for synovitis. CONCLUSION: Low field MRI provides high accuracy for detection and grading of erosions and synovitis, with high field MRI as the standard reference. For bone marrow oedema, specificity is high, but sensitivity only moderate. Low cost, patient compliant, low field dedicated extremity MRI provides similar information on bone erosions and synovitis as expensive high field MRI units.

Ejbjerg B, Narvestad E, Rostrup E, Szkudlarek M, Jacobsen S, Thomsen HS, Østergaard M. · Department of Radiology, Copenhagen University Hospital at Hvidovre, Hvidovre, Denmark. · Arthritis Rheum. · Pubmed #15077291 links to  free full text

Abstract: OBJECTIVE: To explore the presence of changes resembling rheumatoid arthritis erosions and synovitis in metacarpophalangeal (MCP) and wrist joints of healthy individuals on magnetic resonance imaging (MRI) and to compare the MRI findings with conventional radiographic, clinical, and biochemical findings. METHODS: Twenty-eight healthy individuals were studied. Contrast-enhanced MRI and conventional radiography of the dominant wrist and second through fifth MCP joints were performed, coupled with standard clinical assessments and biochemical analyses. MR images were evaluated according to the latest OMERACT (Outcome Measures in Rheumatology Clinical Trials) recommendations with respect to synovitis, erosions, and bone marrow edema. RESULTS: Conventional radiography revealed erosion-like changes in 1 of 224 MCP joint bones (0.4%) and in 1 of 420 wrist joint bones (0.2%). MRI depicted low-grade erosion-like changes in 5 of 224 MCP joint bones (2.2%) and in 7 of 420 wrist joint bones (1.7%), but postcontrast enhancement within the lesion was detected in only 8.3% of these. MRI depicted low-grade synovitis-like changes in 10 of 112 MCP joints (8.9%) and in 8 of 84 assessed wrist areas (9.5%), while only minimal early synovial enhancement was detected by dynamic MRI. Three subjects had elevated serum levels of C-reactive protein, and these subjects displayed 44.5% of the synovitis-like changes and 41.7% of the erosion-like changes. Bone marrow edema-like changes were not found in any joints. CONCLUSION: Changes resembling mild synovitis or small bone erosions are occasionally found in the MCP and wrist joints of healthy controls. Signs of synovitis on dynamic MRI, enhancement within bone erosion-like changes, and signs of bone marrow edema appear rarely or are absent in healthy controls. These signs may thus prove to be very specific in the distinction between arthritic and normal joints.

Jacobsen S. · Department of Rheumatology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark. · Clin Rheumatol. · Pubmed #15045625 No free full text.

Abstract: In 200 patients, 143 women and 57 men, with rheumatoid arthritis (RA), age at onset was related to the presence of IgM rheumatoid factor (RF) and antinuclear antibodies (ANA) in serum at presentation. The patients were stratified into bands of age at onset: <40 years, 40- 60 years, and >60 years. In women, the prevalences of ANA (1:160) were 63.0%, 45.5%, and 31.1% in the respective age bands ( p=0.002), and the prevalences of IgM RF were 85.2%, 72.7% and 66.4%, respectively ( p=0.03). The prevalences of ANA and IgM RF among men were, respectively, 35% and 86% with no association with age at onset. The findings may indicate interactive effects between gender and various pathogenetic factors.

Szkudlarek M, Court-Payen M, Jacobsen S, Klarlund M, Thomsen HS, Østergaard M. · University of Copenhagen Hvidovre Hospital, Denmark. · Arthritis Rheum. · Pubmed #12687537 links to  free full text

Abstract: OBJECTIVE: To evaluate the interobserver agreement of ultrasonographic assessment of finger and toe joints in patients with rheumatoid arthritis (RA) by 2 investigators with different medical backgrounds. METHODS: Ultrasonography and clinical examination were performed on 150 small joints of 30 patients with active RA. A General Electric LOGIQ 500 ultrasound unit with a 7-13-MHz linear array transducer was used. In each patient, 5 preselected small joints (second and third metacarpophalangeal, second proximal interphalangeal, first and second metatarsophalangeal) were examined independently on the same day by 2 ultrasound investigators (an experienced musculoskeletal radiologist and a rheumatologist with limited ultrasound training). Joint effusion, synovial thickening, bone erosions, and power Doppler signal were evaluated in accordance with an introduced 4-grade semiquantitative scoring system, on which the investigators had reached consensus prior to the study. RESULTS: Exact agreement between the 2 observers was seen in 91% of the examinations with regard to bone erosions, in 86% with regard to synovitis, in 79% with regard to joint effusions, and in 87% with regard to power Doppler signal assessments. Corresponding intraclass correlation coefficient values were 0.78, 0.81, 0.61, and 0.72, respectively, while unweighted kappa values were 0.68, 0.63, 0.48, and 0.55, respectively. Ultrasonography showed signs of inflammation in 94 joints, while clinical assessment revealed tenderness and/or swelling in 64 joints. CONCLUSION: An experienced radiologist and a rheumatologist with limited ultrasound training achieved high interobserver agreement rates for the identification of synovitis and bone erosions, using an introduced semiquantitative scoring system for ultrasonography of finger and toe joints in RA. Signs of inflammation were more frequently detected with ultrasound than with clinical examination. Ultrasonography may improve the assessment of RA patients by radiologists and rheumatologists.

Jacobsen S, Madsen HO, Klarlund M, Jensen T, Skjødt H, Jensen KE, Svejgaard A, Garred P, Anonymous00236. · Department of Rheumatology, Hvidovre Hospital, Copenhagen University Hospital, Denmark. · J Rheumatol. · Pubmed #11361219 No free full text.

Abstract: OBJECTIVE: To determine whether variant alleles of the mannose binding lectin (MBL) gene causing low serum concentrations of MBL are associated with increased susceptibility to rheumatoid arthritis (RA) and erosive outcome in an inception cohort of patients with early polyarthritis. METHODS: MBL and HLA-DRB1 alleles were determined by polymerase chain reaction in 68 Danish patients with incident early polyarthritis observed for one year. The associations between MBL and specific HLA-DRB1 genotypes and disease outcomes were analyzed. RESULTS: Among the patients with early polyarthritis 7.4% (5/68) and 41.2% (28/68) were homozygous and heterozygous for MBL variant alleles, compared with 2.8% (7/250) and 34.4% (86/250) of healthy controls (p = 0.09), while the corresponding figures in the patients with RA were 10% (5/50) and 42% (21/50) (p = 0.03), and in the patients with erosive RA 18.8% (3/16) and 35.3% (6/16), respectively (p = 0.004). Patients with early polyarthritis homozygous for MBL variant alleles had an increased risk of having erosive RA at inclusion by a factor of 4.7 (p = 0.02) and after one year by a factor of 3.6 (p = 0.04). MBL deficiency was associated with increased levels of C-reactive protein (CRP) and IgM rheumatoid factor (RF) at inclusion (p < 0.05). HLA-DRB1 alleles were not found to be associated with disease outcome. CONCLUSION: MBL variant alleles appear to be weak susceptibility markers for RA, and patients with early polyarthritis and homozygous for MBL structural variant alleles have a higher risk of developing early erosive RA. These findings, together with the positive association between MBL variant alleles and the increased serum levels of IgM RF and CRP, point at the MBL gene as a relevant locus in the pathophysiology of RA.

Jorgensen CS, Levantino G, Houen G, Jacobsen S, Halberg P, Ullman S, Khamashta MA, Asmussen K, Oxholm P, Jorgensen MK, van Venrooij WJ, Wiik A. · Department of Autoimmunology, Statens Serum Institut, Copenhagen, Denmark. · Lupus. · Pubmed #11035417 No free full text.

Abstract: Annexin XI, a calcyclin-associated protein, has been shown to be identical to a 56,000 Da antigen recognized by antibodies found in sera from patients suffering from systemic autoimmune diseases. In this work hexahistidine-tagged recombinant annexin XI (His6- rAnn XI) was used as antigen in ELISA experiments for determination of autoantibodies to annexin XI in sera of patients with systemic rheumatic autoimmune diseases. Immunoblotting with HeLa cell extract and with His6-rAnn XI as antigen was used for confirmation of positive ELISA results. We found eleven anti-annexin XI positive sera (3.9%) out of 282 sera from patients with systemic rheumatic diseases. The highest number of annexin XI positive sera were found in primary antiphospholipid syndrome (3/17), and in subacute lupus erythematosus (1/6), while lower frequencies of positive sera were found in patients with systemic sclerosis (5/137), rheumatoid arthritis (1/21), and systemic lupus erythematosus (1/58). Sera from healthy donors and patients with chronic infections were negative, except for one Salmonella typhimurium antibody positive serum. Autoantibodies to annexin XI were found to relate to thrombosis, but not to other clinical or laboratory features. A relation between antibodies to annexins and thrombosis has so far only been known for annexin V.

Jacobsen S, Skjødt H, Hørslev-Petersen K, Hansen TM, Sørensen SF, Petersen J, Junker P, Stengaard-Pedersen K. · No affiliation provided · Ugeskr Laeger. · Pubmed #11894713 No free full text.

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