Ewa Berglin | Umeå University (original) (raw)

Papers by Ewa Berglin

Research paper thumbnail of Comorbidity in early rheumatoid arthritis : does inflammation matter?

Research paper thumbnail of Antibodies against citrullinated peptides are associated with clinical and radiological outcomes in patients with early rheumatoid arthritis: a prospective longitudinal inception cohort study

Introduction Anticitrullinated peptide antibody (ACPA) responses for 22 citrullinated peptides in... more Introduction Anticitrullinated peptide antibody (ACPA) responses for 22 citrullinated peptides in patients with early rheumatoid arthritis (RA) were analysed and related to radiological and clinical outcome during the first 2 years in a prospective inception cohort. Methods The ACPA reactivities were assessed in 1022 patients with early RA (symptoms <12 months) using the custom-made microarray chip (Thermo Fisher Scientific, Uppsala, Sweden) in a prospective longitudinal study of observational assessments of Disease Activity Score (DAS28 and its components) and radiology during the first 24 months, accounting for the treatment. Results Frequency of ACPA reactivities varied between 13.3% and 63.1%. Of the anticyclic citrullinated peptide-2 (anti-CCP2) antibody-negative patients, ACPA reactivities were positive in 32.6%. Smoking, human leucocyte antigen-shared epitope (HLA-SE), anti-CCP2/rheumatoid factor, protein tyrosine phosphatase non-receptor type 22 (1858C/T) and DAS28 were s...

Research paper thumbnail of A genetic study on C 5-TRAF 1 and progression of joint damage in rheumatoid arthritis

Introduction: The severity of joint damage progression in rheumatoid arthritis (RA) is heritable.... more Introduction: The severity of joint damage progression in rheumatoid arthritis (RA) is heritable. Several genetic variants have been identified, but together explain only part of the total genetic effect. Variants in Interleukin-6 (IL-6), Interleukin-10 (IL-10), C5-TRAF1, and Fc-receptor-like-3 (FCRL3) have been described to associate with radiographic progression, but results of different studies were incongruent. We aimed to clarify associations of these variants with radiographic progression by evaluating six independent cohorts. Methods: In total 5,895 sets of radiographs of 2,493 RA-patients included in six different independent datasets from the Netherlands, Sweden, Spain and North-America were studied in relation to rs1800795 (IL-6), rs1800896 (IL-10), rs2900180 (C5-TRAF1) and rs7528684 (FCRL3). Associations were tested in the total RA-populations and in anti-citrullinated peptide antibodies (ACPA)-positive and ACPA-negative subgroups per cohort, followed by meta-analyses. Fu...

Research paper thumbnail of Antibodies against citrullinated peptides are associated with clinical and radiological outcomes in patients with early rheumatoid arthritis: a prospective longitudinal inception cohort study

RMD Open

IntroductionAnticitrullinated peptide antibody (ACPA) responses for 22 citrullinated peptides in ... more IntroductionAnticitrullinated peptide antibody (ACPA) responses for 22 citrullinated peptides in patients with early rheumatoid arthritis (RA) were analysed and related to radiological and clinical outcome during the first 2 years in a prospective inception cohort.MethodsThe ACPA reactivities were assessed in 1022 patients with early RA (symptoms <12 months) using the custom-made microarray chip (Thermo Fisher Scientific, Uppsala, Sweden) in a prospective longitudinal study of observational assessments of Disease Activity Score (DAS28 and its components) and radiology during the first 24 months, accounting for the treatment.ResultsFrequency of ACPA reactivities varied between 13.3% and 63.1%. Of the anticyclic citrullinated peptide-2 (anti-CCP2) antibody-negative patients, ACPA reactivities were positive in 32.6%. Smoking, human leucocyte antigen-shared epitope (HLA-SE), anti-CCP2/rheumatoid factor, protein tyrosine phosphatase non-receptor type 22 (1858C/T) and DAS28 were signif...

Research paper thumbnail of Decrease in bone mineral density during three months after diagnosis of early rheumatoid arthritis measured by digital X-ray radiogrammetry predicts radiographic joint damage after one year

Arthritis Research & Therapy

Background: Periarticular osteopenia is an early sign of incipient joint injury in rheumatoid art... more Background: Periarticular osteopenia is an early sign of incipient joint injury in rheumatoid arthritis (RA), but cannot be accurately quantified using conventional radiography. Digital X-ray radiogrammetry (DXR) is a computerized technique to estimate bone mineral density (BMD) from hand radiographs. The aim of this study was to evaluate whether decrease in BMD of the hands (BMD loss), as determined by DXR 3 months after diagnosis, predicts radiographic joint damage after 1 and 2 years in patients with early RA. Methods: Patients (n = 176) with early RA (<12 months after onset of symptoms) from three different Swedish rheumatology centers were consecutively included in the study, and 167 of these patients were included in the analysis. Medication was given in accordance with Swedish guidelines, and the patients were followed for 2 years. Rheumatoid factor and antibodies to cyclic citrullinated peptides (anti-CCP) were measured at baseline, and 28-joint Disease Activity Score (DAS28) was assessed at each visit. Radiographs of the hands and feet were obtained at baseline, 3 months (hands only) and 1 and 2 years. Baseline and 1-year and 2-year radiographs were evaluated by the Larsen score. Radiographic progression was defined as a difference in Larsen score above the smallest detectable change. DXR-BMD was measured at baseline and after 3 months. BMD loss was defined as moderate when the decrease in BMD was between 0.25 and 2.5 mg/cm 2 /month and as severe when the decrease was greater than 2.5 mg/cm 2 /month. Multivariate regression was applied to test the association between DXR-BMD loss and radiographic damage, including adjustments for possible confounders. Results: DXR-BMD loss during the initial 3 months occurred in 59% of the patients (44% moderate, 15% severe): 32 patients (19%) had radiographic progression at 1 year and 45 (35%) at 2 years. In multiple regression analyses, the magnitude of DXR-BMD loss was significantly associated with increase in Larsen score between baseline and 1 year (p = 0.033, adjusted R-squared = 0.069). Conclusion: DXR-BMD loss during the initial 3 months independently predicted radiographic joint damage at 1 year in patients with early RA. Thus, DXR-BMD may be a useful tool to detect ongoing joint damage and thereby to improve individualization of therapy in early RA.

Research paper thumbnail of Predictors of disease onset and progression in early rheumatoid arthritis : A clinical, laboratory and radiological study

Subjects and methods…………………………………………………………………… The Medical Biobank, the Maternity cohort and iden... more Subjects and methods…………………………………………………………………… The Medical Biobank, the Maternity cohort and identification of samples………………. Patients, pre-patients and controls……………………………………………………….... Methods………………………………………………………………………………….... Results and discussions………………………………………………………………….. CR/DXA-study (Paper I)…………………………………………………………………. Discussion (Paper I)………………………………………………………………………. Studies on autoantibodies and HLA SE alleles as predictors of RA onset (Papers II-III)... Discussion (Papers II and III)…………………………………………………………….. Study on autoantibodies and HLA SE alleles as predictors of RA severity and progression (Paper IV)……………………………………………………………………. Discussion (Paper IV)…………………………………………………………………….. Concluding remarks…………………………………………………………………….. Conclusions……………………………………………………………………………….

Research paper thumbnail of Anti-neutrophil cytoplasmic antibodies predate symptom onset of ANCA-associated vasculitis. A case-control study

Research paper thumbnail of Comparison of the 1987 ACR and 2010 ACR/EULAR Classification Criteria for Rheumatoid Arthritis in Clinical Practice

Arthritis and Rheumatism, 2011

Research paper thumbnail of Does Evaluation Of Hand Bone Loss By Digital x-Ray Radiogrammetry Within The First 3 Months After Diagnosis Of Rheumatoid Arthrits Identify Patients At Risk For Radiological Progression?

Arthritis and Rheumatism, 2013

Research paper thumbnail of Comparison of the 1987 ACR and 2010 ACR/EULAR classification criteria for rheumatoid arthritis in clinical practice: a prospective cohort study

Scandinavian Journal of Rheumatology, 2013

To compare application of the 1987 American College of Rheumatology (ACR) and 2010 ACR/European L... more To compare application of the 1987 American College of Rheumatology (ACR) and 2010 ACR/European League Against Rheumatism (EULAR) classification criteria for diagnosing rheumatoid arthritis (RA) in clinical practice. The medical records of patients with early arthritis attending the Rheumatology Department, Umeå University Hospital (n = 1026) were analysed. Patients with synovitis in at least one joint, no diagnosis other than RA being better for explaining the synovitis, and duration of symptoms less than 1 year at first visit, and at least 1 year of follow-up were included consecutively. Fulfilment of the 1987 and 2010 criteria at baseline was evaluated. Sensitivity and specificity for each criterion set, where estimated by using the outcome measures: initiation of methotrexate (MTX) therapy during the first year, and a clinical diagnosis of RA at the 1-year follow-up. Radiographs of hands and feet were evaluated using the Larsen score. The study included 313 patients, of whom 56% fulfilled the 1987 ACR criteria, 74% the 2010 ACR/EULAR criteria, and 53% both sets of criteria at baseline. The sensitivity/specificity for the 1987 and 2010 criteria with MTX within the first year as the outcome measure was 0.68/0.79 and 0.84/0.54, respectively, and with a diagnosis of RA at follow-up 0.72/0.83 and 0.91/0.65, respectively. Older patients (i.e. ≥ 60 years) more often fulfilled the 2010 criteria. Patients who fulfilled the 2010 ACR/EULAR but not the 1987 ACR criteria had a lower Larsen score at inclusion and after 2 years. Compared with the 1987 ACR criteria, the 2010 ACR/EULAR criteria have higher sensitivity but lower specificity, especially in patients aged ≥ 60 years. The 1987 ACR criteria are suggested to predict a more erosive disease.

Research paper thumbnail of Receptor activator of nuclear factor kappa-B ligand (RANKL) but not sclerostin or gene polymorphisms is related to joint destruction in early rheumatoid arthritis

Clinical rheumatology, Jan 11, 2017

The aim of this study was to analyze relationships between receptor activator of nuclear factor k... more The aim of this study was to analyze relationships between receptor activator of nuclear factor kappa-B (RANKL), sclerostin and their gene polymorphisms with radiological progression in patients with early rheumatoid arthritis (RA). Patients with early RA (n = 407, symptomatic <1 year) (ARA criteria) examined radiologically at inclusion and after 24 months were consecutively included. Disease activity score and C-reactive protein were regularly recorded. Sclerostin, RANKL, and anti-CCP2 antibodies were analyzed in plasma at baseline using ELISAs. Data on gene polymorphism for sclerostin and RANKL were extracted from Immunochip analysis. Sex- and age-matched controls (n = 71) were identified from the Medical Biobank of Northern Sweden. The concentration of RANKL was significantly higher in patients compared with controls, median (IQR) 0.56 (0.9) nmol/L and 0.20 (0.25) nmol/L (p < 0.001), and in anti-CCP2-positive patients compared with sero-negative individuals. Sclerostin was ...

Research paper thumbnail of Antibodies to mutated citrullinated vimentin (MCV) are a better predictor of disease activity at 24 months in rheumatoid arthritis than antibodies to cyclic citrullinated peptide (CCP)

Arthritis and Rheumatism, 2006

Research paper thumbnail of Age at onset determines severity and choice of treatment in early rheumatoid arthritis

Arthritis and Rheumatism, 2012

Introduction: Disease activity, severity and comorbidity contribute to increased mortality in pat... more Introduction: Disease activity, severity and comorbidity contribute to increased mortality in patients with rheumatoid arthritis (RA). We evaluated the impact of age at disease onset on prognostic risk factors and treatment in patients with early disease. Methods: In this study, 950 RA patients were followed regularly from the time of inclusion (<12 months from symptom onset) for disease activity (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), tender and/or swollen joints, Visual Analogue Scale pain and global scores, and Disease Activity Score in 28 joints (DAS28)) and function (Health Assessment Questionnaire (HAQ)). Disease severity, measured on the basis of radiographs of the hands and feet (erosions based on Larsen score), extraarticular disease, nodules, and comorbidities and treatment (disease-modifying antirheumatic drugs (DMARDs), corticosteroids, biologics and nonsteroidal anti-inflammatory drugs) were recorded at the time of inclusion and at 5 years. Autoantibodies (rheumatoid factor, antinuclear antibodies and antibodies against cyclic citrullinated peptides (ACPAs)) and genetic markers (human leucocyte antibody (HLA) shared epitope and protein tyrosine phosphatase nonreceptor type 22 (PTPN22)) were analysed at the time of inclusion. Data were stratified as young-onset RA (YORA) and late-onset RA (LORA), which were defined as being below or above the median age at the time of onset of RA (58 years). Results: LORA was associated with lower frequency of ACPA (P < 0.05) and carriage of PTPN22-T variant (P < 0.01), but with greater disease activity at the time of inclusion measured on the basis of ESR (P < 0.001), CRP (P < 0.01) and accumulated disease activity (area under the curve for DAS28 score) at 6 months (P < 0.01), 12 months (P < 0.01) and 24 months (P < 0.05), as well as a higher HAQ score (P < 0.01) compared with YORA patients. At baseline and 24 months, LORA was more often associated with erosions (P < 0.01 for both) and higher Larsen scores (P < 0.001 for both). LORA was more often treated with corticosteroids (P < 0.01) and less often with methotrexate (P < 0.001) and biologics (P < 0.001). YORA was more often associated with early DMARD treatment (P < 0.001). The results of multiple regression analyses supported our findings regarding the impact of age on chosen treatment. Conclusion: YORA patients were more frequently ACPA-positive than LORA patients. LORA was more often associated with erosions, higher Larsen scores, higher disease activity and higher HAQ scores at baseline. Nevertheless, YORA was treated earlier with DMARDs, whilst LORA was more often treated with corticosteroids and less often with DMARDs in early-stage disease. These findings could have implications for the development of comorbidities.

Research paper thumbnail of Antibodies against mutated citrullinated vimentin are a better predictor of disease activity at 24 months in early rheumatoid arthritis than antibodies against cyclic citrullinated peptides

The Journal of rheumatology, 2008

To evaluate the predictive values for disease progression of various antibodies against citrullin... more To evaluate the predictive values for disease progression of various antibodies against citrullinated peptide proteins (ACPA) and their relation to PTPN22 1858C/T polymorphism and HLA-DRB1 alleles in early rheumatoid arthritis (RA). The ACPA, e.g., antibodies against mutated citrullinated vimentin (MCV), cyclic citrullinated peptides (CCP) type 2 and 3 (both of IgG isotype) and 3.1 (of both IgG and IgA isotypes), were analyzed at baseline in patients with early RA (n = 210) and in population controls (n = 102) using an enzyme immunoassay. A receiver-operating characteristic curve was constructed for each antibody. Disease activity [swollen and tender joints, visual analog scale for global health, and erythrocyte sedimentation rate (ESR)] was evaluated at baseline and regularly for 24 months. Radiographs of hands and feet were graded using the Larsen score. Patients with anti-MCV antibodies had significantly less reduction in Disease Activity Score (DAS28) over time (p < 0.01), an...

Research paper thumbnail of Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage

Arthritis Research & Therapy

The presence of a new autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, has ... more The presence of a new autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, has been identified in rheumatoid arthritis (RA). The presence of anti-CarP antibodies was evaluated in samples taken from individuals who subsequently developed RA before and after onset of symptoms and related to previously analysed antibodies against citrullinated peptides (ACPA specificities) and anti-CCP2. A total of 252 individuals, with 423 samples from before onset of symptoms of RA, and 197 population controls were identified as donors to the Medical Biobank of Northern Sweden; 192 of them were also sampled at the time of diagnosis. All samples were analysed for anti-CarP IgG and anti-CCP2 antibodies using ELISAs. Ten different antibody reactivities against citrullinated antigens (ACPA specificities) were analysed using a custom-made microarray based on the ImmunoCAP ISAC system (Phadia). The concentration of anti-CarP antibodies was significantly increased in the pre-symptomatic in...

Research paper thumbnail of Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage

Arthritis research & therapy, Jan 7, 2015

The presence of a new autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, has ... more The presence of a new autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, has been identified in rheumatoid arthritis (RA). The presence of anti-CarP antibodies was evaluated in samples taken from individuals who subsequently developed RA before and after onset of symptoms and related to previously analysed antibodies against citrullinated peptides (ACPA specificities) and anti-CCP2. A total of 252 individuals, with 423 samples from before onset of symptoms of RA, and 197 population controls were identified as donors to the Medical Biobank of Northern Sweden; 192 of them were also sampled at the time of diagnosis. All samples were analysed for anti-CarP IgG and anti-CCP2 antibodies using ELISAs. Ten different antibody reactivities against citrullinated antigens (ACPA specificities) were analysed using a custom-made microarray based on the ImmunoCAP ISAC system (Phadia). The concentration of anti-CarP antibodies was significantly increased in the pre-symptomatic in...

Research paper thumbnail of Receptor activator of nuclear factor kappa B ligand-mediated osteoclastogenesis is elevated in ankylosing spondylitis

Clinical and experimental rheumatology

Ankylosing spondylitis (AS) is an inflammatory arthritis involving the axial skeleton. Decreased ... more Ankylosing spondylitis (AS) is an inflammatory arthritis involving the axial skeleton. Decreased bone mineral density has also been reported in AS patients. This study sought to determine whether osteoclastogenesis and osteoclast activity are increased in AS. Twenty patients with AS were evaluated using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and other clinical parameters. Mononuclear cells were separated out from peripheral blood samples taken from AS patients and normal healthy controls and cultured with monocyte colony stimulating factor and receptor activator of the nuclear factor kappa B ligand (RANKL). Multi-nucleated, tartrate-resistant acid phosphatase stain-positive osteoclasts were counted after 9 days, and the areas of calcium absorption on calcium-coated plates were determined. Osteoclastogenesis was significantly greater in AS patients than in normal controls (number of osteoclasts/1106 mononuclear cells, median, 518.0 vs. 362.5, p=0.036). No dif...

Research paper thumbnail of Antibody response to the human stress protein BiP in rheumatoid arthritis

Rheumatology (Oxford, England), 2004

The human stress protein BiP (immunoglobulin binding protein) has been implicated in the pathogen... more The human stress protein BiP (immunoglobulin binding protein) has been implicated in the pathogenesis of rheumatoid arthritis (RA) since BiP was found to stimulate synovial T-cell proliferation and anti-BiP antibodies are present in the serum of RA patients. The aim of this study was the development of a rapid and reproducible enzyme-linked immunosorbent assay (ELISA) to determine the specificity and sensitivity of anti-BiP antibodies in RA. An ELISA was developed that detected antibodies to BiP. The prevalence of anti-BiP antibodies was determined in sera from patients with early and established RA, sera antedating the onset of RA and sera from patients with other inflammatory and autoimmune diseases and healthy controls. We have confirmed the increased prevalence of antibodies to BiP in the sera of a large cohort of patients with established RA (specificity 71% and sensitivity 73%) and early RA (specificity 65% and sensitivity 66%). In pre-disease sera, median 2.5 yr (interquartil...

Research paper thumbnail of Effect of hydrogen sulfide on the mutagenicity of hydrogen peroxide in Salmonella typhimurium strain TA102

Mutation Research Letters, 1986

Research paper thumbnail of Catalase inhibitiob by sulfide and hydrogen peroxide-induced mutagenicity in Salmonella typhimurium strain TA102

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 1988

The lethal and mutagenic effects of hydrogen peroxide were studied in exponentially growing cultu... more The lethal and mutagenic effects of hydrogen peroxide were studied in exponentially growing cultures of Salmonella typhimurium strain TA102. Exposure of the cultures to non-lethal levels of sodium sulfide significantly increased the lethality and mutagenicity of hydrogen peroxide. The catalase activity was decreased in cells exposed to sodium sulfide, but there were no changes in the cellular levels of superoxide dismutase, glutathione reductase, or NADPH-dependent alkyl hydroperoxide reductase. Hydrogen peroxide-induced mutagenesis and killing of S. typhimurium strain TA102 in the presence of sulfide may in part be explained by an inactivation of catalase by sulfide.

Research paper thumbnail of Comorbidity in early rheumatoid arthritis : does inflammation matter?

Research paper thumbnail of Antibodies against citrullinated peptides are associated with clinical and radiological outcomes in patients with early rheumatoid arthritis: a prospective longitudinal inception cohort study

Introduction Anticitrullinated peptide antibody (ACPA) responses for 22 citrullinated peptides in... more Introduction Anticitrullinated peptide antibody (ACPA) responses for 22 citrullinated peptides in patients with early rheumatoid arthritis (RA) were analysed and related to radiological and clinical outcome during the first 2 years in a prospective inception cohort. Methods The ACPA reactivities were assessed in 1022 patients with early RA (symptoms <12 months) using the custom-made microarray chip (Thermo Fisher Scientific, Uppsala, Sweden) in a prospective longitudinal study of observational assessments of Disease Activity Score (DAS28 and its components) and radiology during the first 24 months, accounting for the treatment. Results Frequency of ACPA reactivities varied between 13.3% and 63.1%. Of the anticyclic citrullinated peptide-2 (anti-CCP2) antibody-negative patients, ACPA reactivities were positive in 32.6%. Smoking, human leucocyte antigen-shared epitope (HLA-SE), anti-CCP2/rheumatoid factor, protein tyrosine phosphatase non-receptor type 22 (1858C/T) and DAS28 were s...

Research paper thumbnail of A genetic study on C 5-TRAF 1 and progression of joint damage in rheumatoid arthritis

Introduction: The severity of joint damage progression in rheumatoid arthritis (RA) is heritable.... more Introduction: The severity of joint damage progression in rheumatoid arthritis (RA) is heritable. Several genetic variants have been identified, but together explain only part of the total genetic effect. Variants in Interleukin-6 (IL-6), Interleukin-10 (IL-10), C5-TRAF1, and Fc-receptor-like-3 (FCRL3) have been described to associate with radiographic progression, but results of different studies were incongruent. We aimed to clarify associations of these variants with radiographic progression by evaluating six independent cohorts. Methods: In total 5,895 sets of radiographs of 2,493 RA-patients included in six different independent datasets from the Netherlands, Sweden, Spain and North-America were studied in relation to rs1800795 (IL-6), rs1800896 (IL-10), rs2900180 (C5-TRAF1) and rs7528684 (FCRL3). Associations were tested in the total RA-populations and in anti-citrullinated peptide antibodies (ACPA)-positive and ACPA-negative subgroups per cohort, followed by meta-analyses. Fu...

Research paper thumbnail of Antibodies against citrullinated peptides are associated with clinical and radiological outcomes in patients with early rheumatoid arthritis: a prospective longitudinal inception cohort study

RMD Open

IntroductionAnticitrullinated peptide antibody (ACPA) responses for 22 citrullinated peptides in ... more IntroductionAnticitrullinated peptide antibody (ACPA) responses for 22 citrullinated peptides in patients with early rheumatoid arthritis (RA) were analysed and related to radiological and clinical outcome during the first 2 years in a prospective inception cohort.MethodsThe ACPA reactivities were assessed in 1022 patients with early RA (symptoms <12 months) using the custom-made microarray chip (Thermo Fisher Scientific, Uppsala, Sweden) in a prospective longitudinal study of observational assessments of Disease Activity Score (DAS28 and its components) and radiology during the first 24 months, accounting for the treatment.ResultsFrequency of ACPA reactivities varied between 13.3% and 63.1%. Of the anticyclic citrullinated peptide-2 (anti-CCP2) antibody-negative patients, ACPA reactivities were positive in 32.6%. Smoking, human leucocyte antigen-shared epitope (HLA-SE), anti-CCP2/rheumatoid factor, protein tyrosine phosphatase non-receptor type 22 (1858C/T) and DAS28 were signif...

Research paper thumbnail of Decrease in bone mineral density during three months after diagnosis of early rheumatoid arthritis measured by digital X-ray radiogrammetry predicts radiographic joint damage after one year

Arthritis Research & Therapy

Background: Periarticular osteopenia is an early sign of incipient joint injury in rheumatoid art... more Background: Periarticular osteopenia is an early sign of incipient joint injury in rheumatoid arthritis (RA), but cannot be accurately quantified using conventional radiography. Digital X-ray radiogrammetry (DXR) is a computerized technique to estimate bone mineral density (BMD) from hand radiographs. The aim of this study was to evaluate whether decrease in BMD of the hands (BMD loss), as determined by DXR 3 months after diagnosis, predicts radiographic joint damage after 1 and 2 years in patients with early RA. Methods: Patients (n = 176) with early RA (<12 months after onset of symptoms) from three different Swedish rheumatology centers were consecutively included in the study, and 167 of these patients were included in the analysis. Medication was given in accordance with Swedish guidelines, and the patients were followed for 2 years. Rheumatoid factor and antibodies to cyclic citrullinated peptides (anti-CCP) were measured at baseline, and 28-joint Disease Activity Score (DAS28) was assessed at each visit. Radiographs of the hands and feet were obtained at baseline, 3 months (hands only) and 1 and 2 years. Baseline and 1-year and 2-year radiographs were evaluated by the Larsen score. Radiographic progression was defined as a difference in Larsen score above the smallest detectable change. DXR-BMD was measured at baseline and after 3 months. BMD loss was defined as moderate when the decrease in BMD was between 0.25 and 2.5 mg/cm 2 /month and as severe when the decrease was greater than 2.5 mg/cm 2 /month. Multivariate regression was applied to test the association between DXR-BMD loss and radiographic damage, including adjustments for possible confounders. Results: DXR-BMD loss during the initial 3 months occurred in 59% of the patients (44% moderate, 15% severe): 32 patients (19%) had radiographic progression at 1 year and 45 (35%) at 2 years. In multiple regression analyses, the magnitude of DXR-BMD loss was significantly associated with increase in Larsen score between baseline and 1 year (p = 0.033, adjusted R-squared = 0.069). Conclusion: DXR-BMD loss during the initial 3 months independently predicted radiographic joint damage at 1 year in patients with early RA. Thus, DXR-BMD may be a useful tool to detect ongoing joint damage and thereby to improve individualization of therapy in early RA.

Research paper thumbnail of Predictors of disease onset and progression in early rheumatoid arthritis : A clinical, laboratory and radiological study

Subjects and methods…………………………………………………………………… The Medical Biobank, the Maternity cohort and iden... more Subjects and methods…………………………………………………………………… The Medical Biobank, the Maternity cohort and identification of samples………………. Patients, pre-patients and controls……………………………………………………….... Methods………………………………………………………………………………….... Results and discussions………………………………………………………………….. CR/DXA-study (Paper I)…………………………………………………………………. Discussion (Paper I)………………………………………………………………………. Studies on autoantibodies and HLA SE alleles as predictors of RA onset (Papers II-III)... Discussion (Papers II and III)…………………………………………………………….. Study on autoantibodies and HLA SE alleles as predictors of RA severity and progression (Paper IV)……………………………………………………………………. Discussion (Paper IV)…………………………………………………………………….. Concluding remarks…………………………………………………………………….. Conclusions……………………………………………………………………………….

Research paper thumbnail of Anti-neutrophil cytoplasmic antibodies predate symptom onset of ANCA-associated vasculitis. A case-control study

Research paper thumbnail of Comparison of the 1987 ACR and 2010 ACR/EULAR Classification Criteria for Rheumatoid Arthritis in Clinical Practice

Arthritis and Rheumatism, 2011

Research paper thumbnail of Does Evaluation Of Hand Bone Loss By Digital x-Ray Radiogrammetry Within The First 3 Months After Diagnosis Of Rheumatoid Arthrits Identify Patients At Risk For Radiological Progression?

Arthritis and Rheumatism, 2013

Research paper thumbnail of Comparison of the 1987 ACR and 2010 ACR/EULAR classification criteria for rheumatoid arthritis in clinical practice: a prospective cohort study

Scandinavian Journal of Rheumatology, 2013

To compare application of the 1987 American College of Rheumatology (ACR) and 2010 ACR/European L... more To compare application of the 1987 American College of Rheumatology (ACR) and 2010 ACR/European League Against Rheumatism (EULAR) classification criteria for diagnosing rheumatoid arthritis (RA) in clinical practice. The medical records of patients with early arthritis attending the Rheumatology Department, Umeå University Hospital (n = 1026) were analysed. Patients with synovitis in at least one joint, no diagnosis other than RA being better for explaining the synovitis, and duration of symptoms less than 1 year at first visit, and at least 1 year of follow-up were included consecutively. Fulfilment of the 1987 and 2010 criteria at baseline was evaluated. Sensitivity and specificity for each criterion set, where estimated by using the outcome measures: initiation of methotrexate (MTX) therapy during the first year, and a clinical diagnosis of RA at the 1-year follow-up. Radiographs of hands and feet were evaluated using the Larsen score. The study included 313 patients, of whom 56% fulfilled the 1987 ACR criteria, 74% the 2010 ACR/EULAR criteria, and 53% both sets of criteria at baseline. The sensitivity/specificity for the 1987 and 2010 criteria with MTX within the first year as the outcome measure was 0.68/0.79 and 0.84/0.54, respectively, and with a diagnosis of RA at follow-up 0.72/0.83 and 0.91/0.65, respectively. Older patients (i.e. ≥ 60 years) more often fulfilled the 2010 criteria. Patients who fulfilled the 2010 ACR/EULAR but not the 1987 ACR criteria had a lower Larsen score at inclusion and after 2 years. Compared with the 1987 ACR criteria, the 2010 ACR/EULAR criteria have higher sensitivity but lower specificity, especially in patients aged ≥ 60 years. The 1987 ACR criteria are suggested to predict a more erosive disease.

Research paper thumbnail of Receptor activator of nuclear factor kappa-B ligand (RANKL) but not sclerostin or gene polymorphisms is related to joint destruction in early rheumatoid arthritis

Clinical rheumatology, Jan 11, 2017

The aim of this study was to analyze relationships between receptor activator of nuclear factor k... more The aim of this study was to analyze relationships between receptor activator of nuclear factor kappa-B (RANKL), sclerostin and their gene polymorphisms with radiological progression in patients with early rheumatoid arthritis (RA). Patients with early RA (n = 407, symptomatic <1 year) (ARA criteria) examined radiologically at inclusion and after 24 months were consecutively included. Disease activity score and C-reactive protein were regularly recorded. Sclerostin, RANKL, and anti-CCP2 antibodies were analyzed in plasma at baseline using ELISAs. Data on gene polymorphism for sclerostin and RANKL were extracted from Immunochip analysis. Sex- and age-matched controls (n = 71) were identified from the Medical Biobank of Northern Sweden. The concentration of RANKL was significantly higher in patients compared with controls, median (IQR) 0.56 (0.9) nmol/L and 0.20 (0.25) nmol/L (p < 0.001), and in anti-CCP2-positive patients compared with sero-negative individuals. Sclerostin was ...

Research paper thumbnail of Antibodies to mutated citrullinated vimentin (MCV) are a better predictor of disease activity at 24 months in rheumatoid arthritis than antibodies to cyclic citrullinated peptide (CCP)

Arthritis and Rheumatism, 2006

Research paper thumbnail of Age at onset determines severity and choice of treatment in early rheumatoid arthritis

Arthritis and Rheumatism, 2012

Introduction: Disease activity, severity and comorbidity contribute to increased mortality in pat... more Introduction: Disease activity, severity and comorbidity contribute to increased mortality in patients with rheumatoid arthritis (RA). We evaluated the impact of age at disease onset on prognostic risk factors and treatment in patients with early disease. Methods: In this study, 950 RA patients were followed regularly from the time of inclusion (<12 months from symptom onset) for disease activity (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), tender and/or swollen joints, Visual Analogue Scale pain and global scores, and Disease Activity Score in 28 joints (DAS28)) and function (Health Assessment Questionnaire (HAQ)). Disease severity, measured on the basis of radiographs of the hands and feet (erosions based on Larsen score), extraarticular disease, nodules, and comorbidities and treatment (disease-modifying antirheumatic drugs (DMARDs), corticosteroids, biologics and nonsteroidal anti-inflammatory drugs) were recorded at the time of inclusion and at 5 years. Autoantibodies (rheumatoid factor, antinuclear antibodies and antibodies against cyclic citrullinated peptides (ACPAs)) and genetic markers (human leucocyte antibody (HLA) shared epitope and protein tyrosine phosphatase nonreceptor type 22 (PTPN22)) were analysed at the time of inclusion. Data were stratified as young-onset RA (YORA) and late-onset RA (LORA), which were defined as being below or above the median age at the time of onset of RA (58 years). Results: LORA was associated with lower frequency of ACPA (P < 0.05) and carriage of PTPN22-T variant (P < 0.01), but with greater disease activity at the time of inclusion measured on the basis of ESR (P < 0.001), CRP (P < 0.01) and accumulated disease activity (area under the curve for DAS28 score) at 6 months (P < 0.01), 12 months (P < 0.01) and 24 months (P < 0.05), as well as a higher HAQ score (P < 0.01) compared with YORA patients. At baseline and 24 months, LORA was more often associated with erosions (P < 0.01 for both) and higher Larsen scores (P < 0.001 for both). LORA was more often treated with corticosteroids (P < 0.01) and less often with methotrexate (P < 0.001) and biologics (P < 0.001). YORA was more often associated with early DMARD treatment (P < 0.001). The results of multiple regression analyses supported our findings regarding the impact of age on chosen treatment. Conclusion: YORA patients were more frequently ACPA-positive than LORA patients. LORA was more often associated with erosions, higher Larsen scores, higher disease activity and higher HAQ scores at baseline. Nevertheless, YORA was treated earlier with DMARDs, whilst LORA was more often treated with corticosteroids and less often with DMARDs in early-stage disease. These findings could have implications for the development of comorbidities.

Research paper thumbnail of Antibodies against mutated citrullinated vimentin are a better predictor of disease activity at 24 months in early rheumatoid arthritis than antibodies against cyclic citrullinated peptides

The Journal of rheumatology, 2008

To evaluate the predictive values for disease progression of various antibodies against citrullin... more To evaluate the predictive values for disease progression of various antibodies against citrullinated peptide proteins (ACPA) and their relation to PTPN22 1858C/T polymorphism and HLA-DRB1 alleles in early rheumatoid arthritis (RA). The ACPA, e.g., antibodies against mutated citrullinated vimentin (MCV), cyclic citrullinated peptides (CCP) type 2 and 3 (both of IgG isotype) and 3.1 (of both IgG and IgA isotypes), were analyzed at baseline in patients with early RA (n = 210) and in population controls (n = 102) using an enzyme immunoassay. A receiver-operating characteristic curve was constructed for each antibody. Disease activity [swollen and tender joints, visual analog scale for global health, and erythrocyte sedimentation rate (ESR)] was evaluated at baseline and regularly for 24 months. Radiographs of hands and feet were graded using the Larsen score. Patients with anti-MCV antibodies had significantly less reduction in Disease Activity Score (DAS28) over time (p < 0.01), an...

Research paper thumbnail of Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage

Arthritis Research & Therapy

The presence of a new autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, has ... more The presence of a new autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, has been identified in rheumatoid arthritis (RA). The presence of anti-CarP antibodies was evaluated in samples taken from individuals who subsequently developed RA before and after onset of symptoms and related to previously analysed antibodies against citrullinated peptides (ACPA specificities) and anti-CCP2. A total of 252 individuals, with 423 samples from before onset of symptoms of RA, and 197 population controls were identified as donors to the Medical Biobank of Northern Sweden; 192 of them were also sampled at the time of diagnosis. All samples were analysed for anti-CarP IgG and anti-CCP2 antibodies using ELISAs. Ten different antibody reactivities against citrullinated antigens (ACPA specificities) were analysed using a custom-made microarray based on the ImmunoCAP ISAC system (Phadia). The concentration of anti-CarP antibodies was significantly increased in the pre-symptomatic in...

Research paper thumbnail of Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage

Arthritis research & therapy, Jan 7, 2015

The presence of a new autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, has ... more The presence of a new autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, has been identified in rheumatoid arthritis (RA). The presence of anti-CarP antibodies was evaluated in samples taken from individuals who subsequently developed RA before and after onset of symptoms and related to previously analysed antibodies against citrullinated peptides (ACPA specificities) and anti-CCP2. A total of 252 individuals, with 423 samples from before onset of symptoms of RA, and 197 population controls were identified as donors to the Medical Biobank of Northern Sweden; 192 of them were also sampled at the time of diagnosis. All samples were analysed for anti-CarP IgG and anti-CCP2 antibodies using ELISAs. Ten different antibody reactivities against citrullinated antigens (ACPA specificities) were analysed using a custom-made microarray based on the ImmunoCAP ISAC system (Phadia). The concentration of anti-CarP antibodies was significantly increased in the pre-symptomatic in...

Research paper thumbnail of Receptor activator of nuclear factor kappa B ligand-mediated osteoclastogenesis is elevated in ankylosing spondylitis

Clinical and experimental rheumatology

Ankylosing spondylitis (AS) is an inflammatory arthritis involving the axial skeleton. Decreased ... more Ankylosing spondylitis (AS) is an inflammatory arthritis involving the axial skeleton. Decreased bone mineral density has also been reported in AS patients. This study sought to determine whether osteoclastogenesis and osteoclast activity are increased in AS. Twenty patients with AS were evaluated using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and other clinical parameters. Mononuclear cells were separated out from peripheral blood samples taken from AS patients and normal healthy controls and cultured with monocyte colony stimulating factor and receptor activator of the nuclear factor kappa B ligand (RANKL). Multi-nucleated, tartrate-resistant acid phosphatase stain-positive osteoclasts were counted after 9 days, and the areas of calcium absorption on calcium-coated plates were determined. Osteoclastogenesis was significantly greater in AS patients than in normal controls (number of osteoclasts/1106 mononuclear cells, median, 518.0 vs. 362.5, p=0.036). No dif...

Research paper thumbnail of Antibody response to the human stress protein BiP in rheumatoid arthritis

Rheumatology (Oxford, England), 2004

The human stress protein BiP (immunoglobulin binding protein) has been implicated in the pathogen... more The human stress protein BiP (immunoglobulin binding protein) has been implicated in the pathogenesis of rheumatoid arthritis (RA) since BiP was found to stimulate synovial T-cell proliferation and anti-BiP antibodies are present in the serum of RA patients. The aim of this study was the development of a rapid and reproducible enzyme-linked immunosorbent assay (ELISA) to determine the specificity and sensitivity of anti-BiP antibodies in RA. An ELISA was developed that detected antibodies to BiP. The prevalence of anti-BiP antibodies was determined in sera from patients with early and established RA, sera antedating the onset of RA and sera from patients with other inflammatory and autoimmune diseases and healthy controls. We have confirmed the increased prevalence of antibodies to BiP in the sera of a large cohort of patients with established RA (specificity 71% and sensitivity 73%) and early RA (specificity 65% and sensitivity 66%). In pre-disease sera, median 2.5 yr (interquartil...

Research paper thumbnail of Effect of hydrogen sulfide on the mutagenicity of hydrogen peroxide in Salmonella typhimurium strain TA102

Mutation Research Letters, 1986

Research paper thumbnail of Catalase inhibitiob by sulfide and hydrogen peroxide-induced mutagenicity in Salmonella typhimurium strain TA102

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 1988

The lethal and mutagenic effects of hydrogen peroxide were studied in exponentially growing cultu... more The lethal and mutagenic effects of hydrogen peroxide were studied in exponentially growing cultures of Salmonella typhimurium strain TA102. Exposure of the cultures to non-lethal levels of sodium sulfide significantly increased the lethality and mutagenicity of hydrogen peroxide. The catalase activity was decreased in cells exposed to sodium sulfide, but there were no changes in the cellular levels of superoxide dismutase, glutathione reductase, or NADPH-dependent alkyl hydroperoxide reductase. Hydrogen peroxide-induced mutagenesis and killing of S. typhimurium strain TA102 in the presence of sulfide may in part be explained by an inactivation of catalase by sulfide.