[Show abstract][Hide abstract] ABSTRACT: 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 individuals compared with controls (P <0.001) and also increased significantly after disease onset (P <0.001). The sensitivity for anti-CarP antibodies in the pre-symptomatic individuals was 13.9% (95% CI: 11 to 17.6) and 42.2% (95% CI: 35.4 to 49.3) following development of RA. Anti-CarP antibody positivity was found in 5.1% to 13.3% of individuals negative for anti-CCP2 or ACPA specificities. Presence of anti-CarP antibodies was significantly related to radiological destruction at baseline, at 24 months and also to radiological change (P <0.05, all).
The results indicate that anti-CarP antibodies are associated with disease development, even after adjusting for the presence of different ACPA fine specificities, and in anti-CCP2 negative individuals and contribute to the identification of a subset of patients with worse radiological progression of the disease independent of ACPA.
[Show abstract][Hide abstract] ABSTRACT: Disease activity, severity and co-morbidity 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 early disease.
In this study, 950 RA patients were followed regularly from inclusion (<12 months from symptom onset) for disease activity (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), tender/swollen joints, visual analogue scale (VAS) pain/global, disease activity score (DAS28)) and function (health assessment questionnaire (HAQ)). Disease severity, measured by radiographs of hands/feet (erosions, Larsen score), extra-articular disease, nodules and co-morbidities and treatment (disease-modifying anti-rheumatic drugs (DMARDs), corticosteroids, biologics, nonsteroidal anti-inflammatory drugs (NSAIDs)) were recorded at inclusion and after 5 years. Autoantibodies (rheumatoid factor (RF), anti-nuclear antibodies (ANA), antibodies against cyclic citrullinated peptides (ACPA)) and genetic markers (human leukocyte antibody (HLA)-shared epitope, protein tyrosine phosphatase nonreceptor type 22 (PTPN22)) were analyzed at inclusion. Data were stratified as young (YORA) and late (LORA) onset RA, defined as being below/above median age (58 years) at onset.
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 inclusion measured as ESR (P < 0.001), CRP (P <0.01) and accumulated disease activity (area under the curve for DAS28) at 6 (P <0.01), 12 (P <0.01) and 24 months (P <0.05), and a higher HAQ score (P <0.01) compared with YORA. At baseline and 24 months, LORA was more often associated with erosions (P <0.01 for both) and a higher Larsen score (P <0.001 for both). LORA was more often treated with corticosteroids (P <0.01), less often with methotrexate (P <0.001) and biologics (P <0.001). YORA was more often associated with early DMARD treatment (P <0.001). Multiple regression analyses supported our findings regarding impact of age on chosen treatment.
YORA patients were more frequently ACPA-positive. LORA was more often associated with erosions, higher Larsen scores, disease activity and HAQ at baseline. Nevertheless, YORA was treated earlier with DMARDs, whilst LORA was more often treated with corticosteroids and with less DMARDs in early disease. This could have implications for development of co-morbidities.
[Show abstract][Hide abstract] ABSTRACT: Antibodies against citrullinated peptides (anti-CCP) and increased levels of cytokines precede the development of rheumatoid arthritis (RA) by several years. Recently, the proteins survivin and Fms-like tyrosine kinase 3 ligand (Flt3L) have been identified as biomarkers of RA associated with joint destruction. Our objective was to investigate the potential of survivin and Flt3L as predictors of RA in samples from patients prior to onset of symptoms.
This study included 47 individuals sampled before onset of RA (median 2.5 years (IQR 4.5) and 155 matched controls, all were donors to the Medical Biobank of Northern Sweden, and 36 RA patients. Levels of anti-CCP, survivin and Flt3L were measured using ELISAs and 29 cytokines/chemokines by multiplex detection.
Levels of survivin were increased in pre-symptomatic individuals compared with controls (P = 0.003), whilst the levels of Flt3L were similar. The frequency of survivin positivity in the pre-symptomatic individuals was increased compared with the controls (36.2 vs.14.2%, P = 0.001) and predicted disease development (odds ratio (OR) =3.4 (95% confidence interval (CI) 1.6-7.2)). The frequency of survivin and Flt3L in RA patients was increased compared with the controls (both, P <0.0001, OR = 12.1 (95% CI, 5.3-27.6) and OR = 11.0 (95% CI, 3.9-30.9), respectively). Anti-CCP positive pre-symptomatic individuals and patients had significantly higher levels of survivin compared with anti-CCP2 negative individuals. In pre-symptomatic individuals, survivin correlated with IL-12, IL-1beta and IL-9 whereas Flt3L correlated to a significantly broader spectrum of cytokines in RA patients.
Proto-oncogene survivin was increased in individuals prior to onset of symptoms of RA and was correlated to cytokines suggesting its role at pre-clinical stages of the disease.
[Show abstract][Hide abstract] ABSTRACT: Background Presence of antibodies against cyclic citrullinated peptides (Anti-CCP2) of IgG, IgA and IgM isotypes has been demonstrated to precede the development of rheumatoid arthritis (RA) by several years. The underlying process for the development of antibodies against certain citrullinated peptides (ACPA) is largely unknown.
Objectives We have investigated antibodies against thirteen citrullinated proteins, besides anti-CCP2, to analyse the development and autoantigen reactivity in the pre-patient phase of RA.
Methods This study comprised 406 individuals, with 717 samples, who were identified before onset of symptoms of RA (median 7.4 years IQR 3.3 – 12.6 years), as donors to the Medical Biobank of Northern Sweden. 204 of them were also sampled at the time of diagnose, and 1305 population controls were identified from the Medical Biobank for analysis of antibodies towards thirteen different citrullinated peptides in plasma; Fibrinogen (Fib) β36-52, Fib 72, Fib 74, Fib α 36-50, Fib α621-635, Fib β60-74, Fib 573,Fib 591, α-enolase, collagen citC1, CCP-1, Vimentin (Vim) 2-17, Vim 60-75 using the microarray based ImmunoCAP ISAC® system (Phadia Diagnostics, Uppsala). All samples were also analysed for anti-CCP2 antibodies with ELISA (Euro-Diagnostics). Cut-off levels were identified by receiver operating characteristic (ROC) curves with 95% specificity as lower limit.
Results The concentrations of all of the analysed antibodies against citrullinated peptides except for antibodies against Vim 60-75, Fib β72, Fib α 591, Fib α 573 and Vim 2-17 using the multiplex assay were significantly increased in pre-diseased individuals compared with controls (p<0.001). Median (IQR) time for the first antibody (Fib α36-50) to appear was 9.8 (11.4) years. The first appearing antibodies (Fib α36-50, Fib α 591, Fib β72 and Vim 60-75) had showed fluctuations in levels over time and only a slight increase after disease onset. Antibodies against Fib β36-52, α-enolase and CCP1 gradually increased in parallel with the highest concentrations before symptom onset. Antibodies against citC1, Fib α621-635 and Fib β74 constituted a third cluster with only a slight increase pre-dating disease onset but a prominent increase after onset. All antibodies had increased concentrations in the RA patients compared with controls (p<0.05- 0.001). The relative risk for future development of RA in individuals with the combination of α-enolase and Fib β36-52 antibodies compared with those having none of the two antibodies all sampled less than 3.35 years before onset of symptoms was 40.4 (CI 95% 19.8-82.3).
Conclusions These results indicate that the development of an ACPA immune response is initially restricted and largely unspecific and expands over time to involve a more specific response with increasing concentrations towards onset of symptoms, most evident for antibodies against α-enolase, Fib β36-52 and CCP1.
Disclosure of Interest None Declared
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies have facilitated the identification of over 30 susceptibility loci for rheumatoid arthritis (RA). However, evidence for a number of potential susceptibility genes have not so far reached genome-wide significance in studies of Caucasian RA.
A cohort of 4286 RA patients from across Europe and 5642 population matched controls were genotyped for 25 SNPs, then combined in a meta-analysis with previously published data.
Significant evidence of association was detected for nine SNPs within the European samples. When meta-analysed with previously published data, 21 SNPs were associated with RA susceptibility. Although SNPs in the PTPN2 gene were previously reported to be associated with RA in both Japanese and European populations, we show genome-wide evidence for a different SNP within this gene associated with RA susceptibility in an independent European population (rs7234029, P = 4.4×10(-9)).
This study provides further genome-wide evidence for the association of the PTPN2 locus (encoding the T cell protein tyrosine phosphastase) with Caucasian RA susceptibility. This finding adds to the growing evidence for PTPN2 being a pan-autoimmune susceptibility gene.
PLoS ONE 06/2013; 8(6):e66456. DOI:10.1371/journal.pone.0066456 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Study Group for Risk Factors for Rheumatoid Arthritis was established by the EULAR Standing Committee on Investigative Rheumatology to facilitate research into the preclinical and earliest clinically apparent phases of rheumatoid arthritis (RA). This report describes the recommendation for terminology to be used to define specific subgroups during different phases of disease, and defines the priorities for research in this area. Terminology was discussed by way of a three-stage structured process: A provisional list of descriptors for each of the possible phases preceding the diagnosis of RA were circulated to members of the study group for review and feedback. Anonymised comments from the members on this list were fed back to participants before a 2-day meeting. 18 participants met to discuss these data, agree terminologies and prioritise important research questions. The study group recommended that, in prospective studies, individuals without RA are described as having: genetic risk factors for RA; environmental risk factors for RA; systemic autoimmunity associated with RA; symptoms without clinical arthritis; unclassified arthritis; which may be used in a combinatorial manner. It was recommended that the prefix 'pre-RA with:' could be used before any/any combination of the five points above but only to describe retrospectively a phase that an individual had progressed through once it was known that they have developed RA. An approach to dating disease onset was recommended. In addition, important areas for research were proposed, including research of other tissues in which an adaptive immune response may be initiated, and the identification of additional risk factors and biomarkers for the development of RA, its progression and the development of extra-articular features. These recommendations provide guidance on approaches to describe phases before the development of RA that will facilitate communication between researchers and comparisons between studies. A number of research questions have been defined, requiring new cohorts to be established and new techniques to be developed to image and collect material from different sites.
Annals of the rheumatic diseases 03/2012; 71(5):638-41. DOI:10.1136/annrheumdis-2011-200990 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rheumatoid factors (RFs) and antibodies against cyclic citrullinated peptides (CCPs) of IgG, IgA and IgM isotype have been shown to precede disease onset by years.
To evaluate serological risk markers in first-degree relatives from multicase families in relation to genetic and environmental risk factors.
51 multicase families consisting of 163 individuals with rheumatoid arthritis (RA) (mean±SD age, 60±14 years; disease duration 21 years; 71.8% female) and with 157 first-degree relatives unaffected by RA (54±17 years; 59.9% female) were recruited. Isotypes of antibodies against CCPs (IgG, IgA and IgM) and RFs (IgM and IgA) were determined using automated enzyme immunoassays. Cut-off levels were established using receiver operating characteristic curves based on values for 100 unrelated healthy controls.
The concentrations and frequencies of all anti-CCP and RF isotypes were significantly increased in first-degree relatives and patients with RA compared with unrelated healthy controls. The relative distribution of IgA and IgM isotypes was higher than IgG in the relatives, whereas the IgG isotype dominated in patients with RA. The patients carried human leucocyte antigen-shared epitope (HLA-SE) significantly more often than the relatives (71.4% vs 53.9%, p=0.01), while the frequency of the PTPN22 T variant was similar. HLA-SE, combined with smoking, was significantly related to all combinations of anti-CCP and RF isotypes in patients with RA. No such relationships were found for the first-degree relatives.
All anti-CCP and RF isotypes analysed occurred more commonly in unaffected first-degree relatives from multicase families than in controls, but with different isotype distribution from patients with RA.
Annals of the rheumatic diseases 11/2011; 71(6):825-9. DOI:10.1136/annrheumdis-2011-200668 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To study the influence of female hormonal factors on the development of rheumatoid arthritis (RA) in relation to the human leucocyte antigen (HLA)-DRB1 shared epitope (SE), the protein tyrosine phosphatase (PTPN22) 1858T variant, anti-citrullinated protein antibodies (ACPAs), and immunoglobulin (Ig)M-rheumatoid factor (IgM-RF).
A case-control study (1:4) was nested within the Medical Biobank of northern Sweden. Females who had subsequently developed RA (n = 70), median of 2.7 years before the onset of symptoms, and matched controls (n = 280) were identified from among the blood donors. A questionnaire concerning previous exposures until disease onset, including hormonal and reproductive factors, and smoking habits was distributed.
Breastfeeding was significantly associated with the development of RA [odds ratio (OR) 4.8, 95% confidence interval (CI) 1.43-15.8]. Increasing time of breastfeeding increased the risk of RA (OR 5.7, 95% CI 1.83-17.95) for breastfeeding ≥ 17 months. In a multiple logistic regression analysis, increasing time of breastfeeding (OR 9.5, 95% CI 2.14-42.43 for ≥ 17 months), seropositivity for ACPAs (OR 19.5, 95% CI 4.47-84.81), and carriage of the PTPN22 1858T variant (OR 3.2, 95% CI 1.36-7.54) remained significant predictors of RA. Users of oral contraceptives (OC) for ≥ 7 years had a decreased risk for development of RA (OR 0.37, 95% CI 0.15-0.93).
A longer duration of breastfeeding increased the risk of developing RA, especially among individuals seropositive for ACPA or IgM-RF or carrying the PTPN22 1858T variant. Use of OC for ≥ 7 years was associated with a decreased risk.
[Show abstract][Hide abstract] ABSTRACT: Genetic factors have a substantial role in determining development of rheumatoid arthritis (RA), and are likely to account for 50-60% of disease susceptibility. Genome-wide association studies have identified non-human leucocyte antigen RA susceptibility loci which associate with RA with low-to-moderate risk.
To investigate recently identified RA susceptibility markers using cohorts from six European countries, and perform a meta-analysis including previously published results.
3311 DNA samples were collected from patients from six countries (UK, Germany, France, Greece, Sweden and Denmark). Genotype data or DNA samples for 3709 controls were collected from four countries (not Sweden or Denmark). Eighteen single nucleotide polymorphisms (SNPs) were genotyped using Sequenom MassArray technology. Samples with a >95% success rate and only those SNPs with a genotype success rate of >95% were included in the analysis. Scandinavian patient data were pooled and previously published Swedish control data were accessed as a comparison group. Meta-analysis was used to combine results from this study with all previously published data.
After quality control, 3209 patients and 3692 controls were included in the study. Eight markers (ie, rs1160542 (AFF3), rs1678542 (KIF5A), rs2476601 (PTPN22), rs3087243 (CTLA4), rs4810485 (CD40), rs5029937 (6q23), rs10760130 (TRAF1/C5) and rs7574865 (STAT4)) were significantly associated with RA by meta-analysis. All 18 markers were associated with RA when previously published studies were incorporated in the analysis. Data from this study increased the significance for association with RA and nine markers.
In a large European RA cohort further evidence for the association of 18 markers with RA development has been obtained.
Annals of the rheumatic diseases 05/2010; 69(8):1548-53. DOI:10.1136/ard.2009.121020 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To identify whether cytokines, cytokine-related factors, and chemokines are up-regulated prior to the development of rheumatoid arthritis (RA).
A nested case-control study was performed in 86 individuals who had donated blood samples before experiencing any symptoms of disease (pre-patients) and 256 matched control subjects (1:3 ratio). In 69 of the pre-patients, blood samples were also obtained at the time of the diagnosis of RA. The plasma levels of 30 cytokines, related factors, and chemokines were measured using a multiplex system.
The levels of several of the cytokines, cytokine receptors, and chemokines were significantly increased in individuals before disease onset compared with the levels in control subjects; i.e., those representing signs of general immune activation (interleukin-1beta [IL-1beta], IL-2, IL-6, IL-1 receptor antagonist, and tumor necrosis factor), activation of Th1 cells (interferon-gamma, IL-12), Th2 cells (IL-4, eotaxin), Treg cells (IL-10), bone marrow-derived factors (IL-7, granulocyte-macrophage colony-stimulating factor, and granulocyte colony-stimulating factor), as well as chemokines (monocyte chemotactic protein 1 and macrophage inflammatory protein 1alpha). The levels were particularly increased in anti-cyclic citrullinated peptide antibody- and rheumatoid factor-positive individuals, and the concentration of most of these increased further after disease onset. The concentration of IL-17 in individuals before disease onset was significantly higher than that in patients after disease onset. Individuals in whom RA subsequently developed were discriminated from control subjects mainly by the presence of Th1 cells, Th2 cells, and Treg cell-related cytokines, while chemokines, stromal cell-derived cytokines, and angiogenic-related markers separated patients after the development of RA from individuals before the onset of RA.
Individuals in whom RA later developed had significantly increased levels of several cytokines, cytokine-related factors, and chemokines representing the adaptive immune system (Th1, Th2, and Treg cell-related factors); after disease onset, the involvement and activation of the immune system was more general and widespread.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to investigate whether homocysteine is linked to atherothrombotic (AT) events in patients with rheumatoid arthritis (RA).
Analysis of homocysteine (Hcy) levels was carried out in 235 consecutive RA patients. They were followed-up for 6.5 years or until death, with analysis of AT risk factors and the type and length of DMARD and corticosteroid treatment. The disease history before inclusion was collected. Six categories of AT events were defined. In addition, the diagnosis of the patients at follow-up was co-analyzed with the nationwide population-based Swedish Inpatient Register and Death Register to certify all events.
The Hcy level was found to be higher in males (p<0.05) and increased with age (p<0.001). Patients with folic acid supplementation had significantly lower levels, while those on corticosteroids had higher levels. High Hcy levels predicted AT events (n=48) during a 6.5-year follow-up adjusted for age and male sex in a logistic regression analysis.
In this study, RA patients on folic acid had lower Hcy levels. High Hcy levels (in addition to age, sex and diabetes) predicted AT event prospectively.
Clinical and experimental rheumatology 01/2009; 27(5):822-5. · 2.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate a possible systemic effect of joint inflammation in contrast to skin disease only, by measuring IL-6 and IL-2sRalpha.
Two hundred and nineteen patients (111 male / 108 female, age 50.4+/-14.5 yrs (mean+/-SD)) with psoriasis were clinically and laboratory examined. 134 patients had inflammatory joint manifestations defined as peripheral arthritis and/or axial disease, of whom 37 had measurable inflammation, defined as ESR >25 mm/h and/or CRP >15 mg/L.
Interleukin-6 was significantly higher in patients with joint disease and measurable inflammation ((median, Q1-Q3) 4.07, 0.92-14.60), and in patients without measured inflammation (1.22, 0.70-3.46), compared to patients with skin disease only (0.70, 0.70-1.73, p<0.001 and p=0.002 respectively). The difference between the two groups of patients with inflammatory joint manifestations was significant (p=0.001). The levels of IL-6 correlated with the actual number of joints affected with arthritis (p<0.001; rs=0.248), ESR (p<0.001; rs=0.459), CRP (p<0.001; rs=0.314) and IL-2sRalpha (p=0.002; rs=0.210). The levels of IL-2sRalpha. did not differ between the 3 groups.
In this study, IL-6 was significantly higher in patients with psoriasis and inflammatory joint disease with or without routine measurable inflammatory activity compared with patients having psoriasis of the skin. We found that patients with psoriasis and joint inflammation may have systemic effects that could be captured by serum measurements of IL-6. Soluble IL-2Ralpha was not a marker of inflammation in this study.
Clinical and experimental rheumatology 01/2009; 27(1):120-3. · 2.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To analyse the effects of infliximab infusions on serum levels of lipids in patients with rheumatoid arthritis (RA) treated for 2 years.
Fifty-two patients (41 females and 11 males) with RA undergoing infliximab treatment (3 mg/kg) were consecutively recruited into the study. The mean (+/-SD) age of the patients was 54.6+/-12.5 years and mean disease duration was 14.1+/-8.6 years. Blood was sampled before infusion at baseline, and at 3, 6, 12, 18 and 24 months. Forty-one of the patients were also treated with methotrexate, 13 with other disease-modifying anti-rheumatic drugs (DMARDs) and 28 with prednisolone (<10 mg daily). For comparison, lipid levels were followed for 2 years in 70 consecutively included patients with early RA during treatment with conventional DMARDs.
There was an initial increase in plasma levels of cholesterol, high density lipoprotein (HDL)-cholesterol, low density lipoprotein (LDL)-cholesterol, and LDL/HDL and total/HDL cholesterol ratios. However, after 3 months HDL-cholesterol decreased significantly, followed after 6 months by cholesterol and LDL-cholesterol. The LDL/HDL and total/HDL-cholesterol ratios remained significantly raised. HDL-cholesterol increased and the ratios improved in patients with early RA receiving conventional treatment. The changes over time differed significantly between the patient groups.
During infliximab infusion a pro-atherogenic lipid profile developed despite reduced inflammatory activity. The long-term decrease in HDL-cholesterol was unexpected considering the known effects of tumour necrosis factor-alpha (TNFalpha).
[Show abstract][Hide abstract] ABSTRACT: To compare the prevalence of anti-CCP antibodies in psoriatic patients with and without joint inflammation, patients with early RA, and controls.
Anti-CCP antibodies (cut off level 5 U/ml) were measured in 160 patients with psoriatic arthritis (PsA), 146 patients with psoriasis but no arthritic disease, 101 patients with early RA, and 102 healthy controls by ELISA.
11 (7%) patients with PsA, 75 (74%) patients with early RA, 2 (2%) healthy controls (2%), and 1 (0.7%) patient with psoriasis without arthritis had anti-CCP antibodies above the cut off level. The presence of anti-CCP antibodies was not related to radiological changes and/or deformity and functional impairment in PsA. 8/11 patients with PsA and anti-CCP antibodies had a polyarthritic disease, and all fulfilled the ACR criteria for RA at 4 year follow up. Five of these 8 patients also had manifestations such as dactylitis, DIP involvement, radiological changes associated with PsA, and/or enthesitis. In multiple logistic regression analysis with polyarthritis as the dependent variable, anti-CCP antibodies and rheumatoid factor significantly distinguished RA from PsA.
Anti-CCP antibodies were more prevalent in patients with PsA than in patients with psoriasis without arthritis, but less prevalent than in patients with early RA. Patients with PsA positive for anti-CCP antibodies more often had polyarthritic disease, but the presence of anti-CCP antibodies did not relate to radiological changes and/or deformity and functional impairment.
Annals of the Rheumatic Diseases 04/2006; 65(3):398-400. DOI:10.1136/ard.2005.040998 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To analyze the association of several autoimmune disease susceptibility loci in a population of patients with psoriasis and defined joint disease from northern Sweden.
One hundred twenty patients with psoriasis and defined joint disease were examined clinically, radiologically, and with laboratory-based analyses. Disease classification was based on peripheral and/or axial engagement. The tumor necrosis factor (TNF) locus, 1q21 (PSORS4), 3q21 (PSORS5), 8q24, 16q21, and the CTLA4 gene were analyzed using a total of 38 microsatellite markers and 2 single nucleotide polymorphisms (SNP). Ninety-four controls with the same ethnic background as the patients were randomly selected from the same region of Sweden.
An association was found with one of the markers in the TNFB locus within the HLA region (p = 0.012, pc = 0.024). Three markers at the PSORS4 locus on chromosome 1q21 and 2 markers at the 8q24 locus showed nominal p values of < 0.05. After applying the Bonferroni correction for multiple analyses these markers did not reach significance. No other marker showed significant association. In a subgroup of the patients, possible linkage disequilibrium between the TNFB123 and HLA-B antigens, B17, B27, B37, B44, and B62 was analyzed. A significant linkage (p = 0.0001) was found.
We identified an association between psoriatic arthritis and one of the microsatellite markers within the TNFB locus at the HLA region on chromosome 6. Linkage disequilibrium between TNFB123 and certain HLA-B antigens was found.
The Journal of Rheumatology 12/2004; 31(11):2230-5. · 3.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An increased mortality due to cardiovascular disease (CVD) has been demonstrated in rheumatoid arthritis (RA). Data also implicate an accelerated atherosclerotic process in RA. Established cardiovascular risk factors are not prominent, but there is some support for an increased prevalence of hypertension and of dyslipidemia, with decreased levels of LDL- as well as HDL-cholesterol in RA. The inflammatory activity seems to be an important predictor of CVD, per se or by mechanisms like endothelial activation, metabolic processes and the hemostatic system. Dampening of the inflammatory activity seems to have a favorable impact on the progression of CVD in RA.
[Show abstract][Hide abstract] ABSTRACT: Antibodies against cyclic citrullinated peptide (CCP) and rheumatoid factors (RFs) have been demonstrated to predate the onset of rheumatoid arthritis (RA) by years. A nested case-control study was performed within the Northern Sweden Health and Disease study cohort to analyse the presence of shared epitope (SE) genes, defined as HLA-DRB1*0404 or DRB1*0401, and of anti-CCP antibodies and RFs in individuals who subsequently developed RA. Patients with RA were identified from among blood donors whose samples had been collected years before the onset of symptoms. Controls matched for age, sex, and date of sampling were selected randomly from the same cohort. The SE genes were identified by polymerase chain reaction sequence-specific primers. Anti-CCP2 antibodies and RFs were determined using enzyme immunoassays. Fifty-nine individuals with RA were identified as blood donors, with a median antedating time of 2.0 years (interquartile range 0.9-3.9 years) before presenting with symptoms of RA. The sensitivity for SE as a diagnostic indicator for RA was 60% and the specificity was 64%. The corresponding figures for anti-CCP antibodies were 37% and 98%, and for RFs, 17-42% and 94%, respectively. In a logistic regression analysis, SE (odds ratio [OR] = 2.35), anti-CCP antibodies (OR = 15.9), and IgA-RF (OR = 6.8) significantly predicted RA. In a combination model analysis, anti-CCP antibodies combined with SE had the highest OR (66.8, 95% confidence interval 8.3-539.4) in predicting RA, compared with anti-CCP antibodies without SE (OR = 25.01, 95% confidence interval 2.8-222.2) or SE without anti-CCP antibodies (OR = 1.9, 95% confidence interval 0.9-4.2). This study showed that the presence of anti-CCP antibodies together with SE gene carriage is associated with a very high relative risk for future development of RA.
[Show abstract][Hide abstract] ABSTRACT: To identify predictors for radiological and functional outcome and bone loss in the hands in early rheumatoid arthritis (RA) during the first 2 yr of disease and to study the relationship between these variables.
An inception cohort of consecutively recruited patients was examined at baseline and after 12 and 24 months using X-rays of hands and feet, clinical [28-joint count, Health Assessment Questionnaire (HAQ), global visual analogue scale (VAS), grip strength] and laboratory (erythrocyte sedimentation rate, C-reactive protein, markers of bone formation and resorption) measurements and dual-energy X-ray absorptiometry measurements of the hands.
Joint destruction increased significantly during the study, with the Larsen score at baseline as the strongest predictor. Radiological progression and bone loss over 24 months were significantly retarded in patients responding to therapy. The effects of the shared epitope and initial high inflammatory activity on radiological progression were overridden by the therapeutic response. Radiological progression correlated significantly with bone loss. Global VAS, Larsen score and HAQ at inclusion significantly predicted change in HAQ over time.
Radiological progression and bone loss were retarded by early therapeutic response. Bone loss was related to radiological progression.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: To examine the prevalence of inflammatory manifestations, such as peripheral arthritis, axial disease, undifferentiated spondyloarthropathy (uSpA) and enthesopathies in patients with psoriasis, and to evaluate a psoriatic and arthritic questionnaire (PAQ) to identify patients with arthritis. Methods. An evaluation of a questionnaire (PAQ) in a hospital- and community-based population of 276 psoriatic patients, and clinical, radiological, and laboratory examination of the 202 patients answering the questionnaire and willing to participate in the subsequent study. Results. Ninety-seven patients (48%) were identified as having, or having had, inflammatory manifestations (peripheral arthritis, axial disease, uSpA, and enthesopathies). Sixty-seven patients (33%) had peripheral arthritis and/or axial disease, 30 of whom had not previously been diagnosed. A total PAQ score of 4 out of 8 was the best cutoff value detecting arthritis with a sensitivity of 60% and a specificity of 62.2%. A positive answer to the question "Have you ever thought you might have arthritis?" in combination with morning stiffness in peripheral joints for at least 60 min, had a sensitivity of 30% and a specificity of 91.1% and was significantly associated with peripheral arthritis and/or axial disease in multiple logistic regression analysis. Conclusion. We found a high prevalence of inflammatory joint/axial disease in this group of psoriatic patients. Almost half the patients with peripheral arthritis and/or axial disease had not previously been diagnosed. The PAQ did not, either as a total score or by combining questions, discriminate for arthritis in this population with psoriasis.
The Journal of Rheumatology 01/2003; 29(12):2577-82. · 3.19 Impact Factor