Sigrid Ødegård

High anti-cyclic citrullinated peptide levels and an algorithm of four variables predict radiographic progression in patients with rheumatoid arthritis: results from a 10-year longitudinal study

Objectives: New effective therapies with particularly good effect on joint destruction have highlighted the need for reliable predictors of radiographic progression in rheumatoid arthritis (RA). Our objective was to assess the combined predictive role of a set of laboratory markers with regard to 10-year radiographic progression, and to examine the effect of anti-cyclic citrullinated peptide (anti-CCP) level. Methods: A cohort of 238 patients with RA was followed longitudinally for 10 years with the collection of clinical data and serum samples. 125 patients with radiographs of the hands available at both baseline and after 10 years were included in this study. Radiographs were scored according to the van der Heijde modified Sharp score. Baseline sera were analysed for C-reactive protein, erythrocyte sedimentation rate (ESR), anti-CCP, IgA rheumatoid factor (RF) and IgM RF. Logistic regression analyses were used to identify predictors of radiographic progression and to examine the effect of anti-CCP level. Results: Anti-CCP (OR 4.0; 95% CI 1.6 to 10.0) was the strongest independent predictor of radiographic progression. Female gender (OR 3.3; 95% CI 1.3 to 7.6), high ESR (OR 3.2; 95% CI 1.2 to 7.6) and a positive IgM RF (OR 3.1; 95% CI 1.2 to 7.9) were also independent predictors. Compared with the anti-CCP-negative patients, patients with low to moderate levels of anti-CCP (OR 2.6; 95% CI 0.9 to 7.2) and patients with high levels of anti-CCP (OR 9.9; 95% CI 2.7 to 36.7) were more likely to develop radiographic progression. Conclusions: Anti-CCP, IgM RF, ESR and female gender were independent predictors of radiographic progression and could be combined into an algorithm for better prediction. Patients with high levels of anti-CCP were especially prone to radiographic progression, indicating that the anti-CCP level may add prognostic information.

Epidemiological Aspects of Rheumatoid Arthritis

Abstract:  Many rheumatic diseases, including rheumatoid arthrits (RA) are more frequent in females than males. The objective of this article was to examine the female versus male perspective regarding prevalence/incidence, etiological factors, disease severity/outcomes, access to therapy and therapeutic responses. We also present results from some new analyses from the patient registers in Oslo to supplement existing literature in this area. We found that the prevalence of RA is higher in females than males, the incidence is 4–5 times higher below the age of 50, but above 60–70 years the female/male ratio is only about 2. Smoking is a consistent predictor of RA in males, but findings have been more inconsistent in females. We could not confirm that health status is worse in females than males when corrections were made for different disease duration and for the underlying tendency of healthy females to report worse subjective health status than males. Some studies and data presented here indicate that females have less access to health services. We also found that female sex reduces the likelihood of achiving treatment response with methotrexate and anti‐tumor necrosis factor (anti‐TNF) drugs by 30–50%. More research is needed to fully describe the differences between males and females regarding epidemiological data.

Cortical hand bone loss after 1 year in early rheumatoid arthritis predicts radiographic hand joint damage at 5-year and 10-year follow-up

Objective: To examine 1-year hand bone loss in early rheumatoid arthritis (RA) as a predictor of radiographic damage at 5-year and 10-year follow-up Methods: A total of 136 patients with RA (disease duration 0–4 years) were followed for 10 years with clinical data and hand radiographs. Joint damage was scored according to the van der Heijde modification of the Sharp method (vdH Sharp score) and hand bone mineral density (BMD) was measured by digital x ray radiogrammetry (DXR). Group comparisons, correlation analyses and multivariate analyses were performed to evaluate the relationship between hand bone loss and radiographic joint damage. Results: Patients with hand BMD loss at 1 year had a higher median increase in vdH Sharp score compared to patients without loss at 5 years (12 vs 2, p = 0.001) and 10 years (22 vs 4, p = 0.002). In a linear regression model adjusting for age, gender, baseline C-reactive protein (CRP), anti-cyclic citrullinated peptide (CCP), IgM rheumatoid factor (RF) and radiographic damage, absolute hand DXR-BMD loss at 1 year was an independent predictor of radiographic outcome at 5 years (p<0.01) and 10 years (p = 0.02). In a logistic regression model the odds ratio (95% CI) for radiographic progression among patients with hand BMD loss was 3.5 (1.4 to 8.8) and 3.5 (1.4 to 8.4) at 5 and 10 years, respectively. Conclusion: Early hand bone loss measured by DXR-BMD is an independent predictor of subsequent radiographic damage. Our findings support that quantitative hand bone loss in RA precedes radiographic joint damage and may be used as a tool for assessment of bone involvement in RA.

Calprotectin (a major leucocyte protein) is strongly and independently correlated with joint inflammation and damage in rheumatoid arthritis

Objective: Calprotectin is a major leucocyte protein, shown to correlate well with laboratory and clinical assessments in several inflammatory rheumatic diseases, and large concentrations of calprotectin have been found in synovial fluid from patients with rheumatoid arthritis (RA). The objective of the present study was to examine correlations between calprotectin and joint damage. Methods: 145 patients with RA were analysed cross sectionally with laboratory (calprotectin, C reactive protein (CRP), and erythrocyte sedimentation rate (ESR)), clinical (28 joint counts (tender, swollen), physician global VAS, DAS28 and RA Articular Damage score (RAAD)), and radiographic (plain hand radiographs; modified Sharp’s method) measurements, on the same day. Results: Calprotectin showed a highly significant correlation with measures of joint damage; modified Sharp score r = 0.43 (p<0.001) and RAAD r = 0.40 (p<0.001). The association with modified Sharp score and RAAD score was maintained after adjustment for CRP, ESR, rheumatoid factor, DAS28, sex, and age in a multiple regression analysis (p = 0.018 and p = 0.04, respectively), while neither CRP nor ESR showed any independent associations. Highly significant correlations (p<0.001) were also found between calprotectin and both laboratory and clinical markers of inflammation. Conclusion: Calprotectin was found to significantly and independently explain the variation in the radiological and clinical assessments of joint damage. Longitudinal studies are required to examine whether calprotectin may predict the progression of joint damage in RA.

Prediction of radiographic progression in rheumatoid arthritis and the role of antibodies against mutated citrullinated vimentin: results from a 10-year prospective study

Objectives: Anti-citrullinated peptide antibodies (ACPAs) are established as useful predictors of radiographic progression in rheumatoid arthritis (RA). The main objective of this study was to test the prognostic capacity of the recently developed test for anti-mutated citrullinated vimentin (anti-MCV). Methods: A cohort of 238 patients with RA was followed longitudinally for 10 years; 125 patients with complete x ray sets were included in the main analyses. Radiographs were scored according to the van der Heijde modified Sharp score (SHS). Patients were analysed for anti-MCV and anti-cyclic citrullinated peptide (CCP), and were genotyped for human leukocyte antigen (HLA)-DRB1 “shared epitope” (SE) and protein tyrosine phosphatase, non-receptor type 22 (PTPN22) 1858T. Results: Anti-MCV and anti-CCP were strongly associated with regard to status and level. Both antibodies were associated with SE, but only anti-MCV was significantly associated with PTPN22 1858T. A positive anti-MCV test increased the odds of radiographic progression by 7.3 (95% confidence interval (CI) 3.2 to 16.5) compared to 5.7 (95% CI 2.6 to 12.5) for a positive anti-CCP. Presence of MCV antibodies gave an average increase in the total SHS of 30 U compared to an average increase of 25 U for the presence of CCP antibodies. Anti-MCVs were more strongly associated to progression in erosions than joint space narrowing. Associations remained after adjustment for other predictors of radiographic progression. The odds of progression increased with increasing anti-MCV level. Conclusions: Presence of anti-MCV predicted joint damage, and the strength of this prediction was at least as strong as for anti-CCP. Antibody status showed a stronger association to bone than to cartilage destruction. This study also indicates that higher anti-MCV levels add prognostic information compared to their mere presence or absence.

Work disability in rheumatoid arthritis is predicted by physical and psychological health status: a 7‐year study from the Oslo RA register

Objective: To explore the prevalence of work disability (WD) and to identify bio‐psychological factors that predicts future WD in rheumatoid arthritis (RA) over a 7‐year period. Methods: Patients were selected from the Oslo RA register. The prevalence of WD was studied cross‐sectionally among respondents <67 years (n = 526) in a postal survey. Mean age (SD) was 51.1 (11.9) years, mean disease duration 11.3 (9.4) years, and 49% of patients were RF‐positive. The patients studied for predictive factors for WD were respondents in postal surveys both at baseline and at the 7‐year follow‐up, in work at baseline and still in working age (<67 years) at follow‐up (n = 159). Mean age at baseline (SD) was 44.5 (9.7) years, mean disease duration 8.4 (6.6) years, mean years of formal education 12.7 (3.1) years, 48% were RF‐positive. Assessments included socio‐demographic variables and health status measures (MHAQ, AIMS2, SF‐36, fatigue and pain on VAS 0–100 mm, self efficacy, and RAI as a measure for helplessness). Results: Among the 526 respondents at baseline <67 years, the prevalence of WD was 40%. A high level of education was a predictor of reduced risk of work disability [odds ratio (OR) = 0.4, 95% confidence interval (CI) 0.1; 0.9], while female gender (OR 3.0, 95% CI 1.1; 8.0), physical disability (MHAQ‐score) (OR = 3.9, 95% CI 1.2; 12.5) and helplessness over median RAI‐score (OR = 3.0, 95% CI 1.4; 6.7) were independent predictors of increased risk for new work disability over 7 years. Conclusion: Physical disability, increased helplessness, low formal education, and female gender were found to be independent risk factors for new work disability over the 7‐year study period.

Pain and psychological health status over a 10-year period in patients with recent onset rheumatoid arthritis

Objective: To examine rheumatoid arthritis (RA) with short disease duration over 10 years, and to identify factors that are associated with the course of pain, depression and anxiety. Methods: A cohort of 238 patients with RA (age 20–70 years, mean disease duration 2.3 years, 68% rheumatoid factor positive) was followed with assessments at baseline and after 1, 2, 5 and 10 years. Self-reported health status was assessed by pain on a 100 mm visual analogue scale, the Arthritis Impact Measurement Scales (AIMS), the 28-item version of General Health Questionnaires, and the Health Assessment Questionnaire. We also examined the erythrocyte sedimentation ratio, grip strength (kg) and radiographic progression of the hands (van der Heijde modified Sharp score). Repeated measures analyses of variance were used to explore the effect of time on measures of outcome among completers, whereas repeated measures analyses using a mixed model were applied to identify factors that were longitudinally associated with pain, depression and anxiety. Results: At the various assessment points 30% had a visual analogue scale pain score of ⩾40 mm, 5–13% had an AIMS depression score of ⩾4.0 and 20–30% had an AIMS anxiety score of ⩾4.0. The perceived level of pain was explained longitudinally by anxiety, disease activity, physical function and female gender, depression by high disease activity and anxiety, whereas anxiety was explained by low disease activity and depression. Conclusion: More patients had increased levels of anxiety (20–30%) than increased levels of depression (5–13%). Several factors, including anxiety, but not depression, were associated with the course of pain.

Calprotectin (a major S100 leucocyte protein) predicts 10-year radiographic progression in patients with rheumatoid arthritis

Background: Plasma levels of calprotectin, a major S100 leucocyte protein, are cross-sectionally associated with clinical and laboratory markers of inflammation and with radiographic damage in rheumatoid arthritis (RA). High amounts of calprotectin are found in synovial fluid from patients with RA. Objective: To examine whether calprotectin might be an independent predictor of joint destruction over time. Methods: 124 patients with RA were assessed at baseline and after 10 years with inflammatory markers (calprotectin, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)), serological variables (antibodies to cyclic citrullinated peptide (anti-CCP), IgA rheumatoid factor (RF) and IgM RF) and radiographic and clinical assessments of joint damage (hand radiographs and Rheumatoid Arthritis Articular Damage (RAAD) score). Progression of radiographic damage was assessed according to the van der Heijde modified Sharp score. Results: At both examinations the highest calprotectin levels were found in patients positive for anti-CCP, IgA and IgM RF. Calprotectin had moderate to good correlations with inflammatory and serological markers (r = 0.41–0.67). Patients with normal baseline calprotectin levels had a lower degree of joint damage. High univariate associations were found between baseline calprotectin levels and progression in the Sharp score as well as the RAAD score. Baseline calprotectin was independently associated with progression in the Sharp score and with the RAAD score in multiple linear regression analyses, including baseline levels of CRP, ESR, anti-CCP in addition to demographic variables. Conclusion: Calprotectin was an independent predictor of clinical and radiographic joint damage after 10 years. These findings support the proposal that calprotectin may be a prognostic biomarker for erosive disease in patients with RA.

Cartilage and Bone Biomarkers in Rheumatoid Arthritis: Prediction of 10-year Radiographic Progression

Objective. As current predictors of joint destruction have low specificity, serological biomarkers reflecting bone and cartilage destruction have been proposed as tools in assessing prognosis of rheumatoid arthritis (RA). We examined whether serum concentrations of a panel of biomarkers could predict radiographic progression in patients with RA. Methods. A cohort of 238 patients with RA was followed longitudinally for 10 years with collection of clinical data and serum samples. These analyses focus on the 136 patients with radiographs of the hands available at baseline and at 5 and/or 10 years. Radiographs were scored according to the van der Heijde-modified Sharp score (SHS). Baseline sera were analyzed for receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), human cartilage glycoprotein-39 (YKL-40), C2C, collagen cross-linked C-telopeptide (CTX-I), and cartilage oligomeric matrix protein (COMP). Multivariate linear and logistic regression analyses were used to identify predictors of radiographic progression. Results. Baseline CTX-I levels were higher in progressors [0.41 ng/ml (interquartile range 0.31–0.75)] than in nonprogressors [0.32 ng/ml (IQR 0.21–0.49)], and were independently associated with 10-year change in radiographic damage score [ß = 16.4 (IQR 5.7–27.1)]. We found no association between radiographic progression and baseline serum levels of RANKL, OPG, C2C, YKL-40, or COMP. Conclusion. This longterm followup study of patients with RA indicates a relationship between elevated CTX-I levels in serum and subsequent joint destruction. This association was, however, weak, and our study does not support that serum CTX-I or any of the other tested biomarkers will serve as more useful prognostic markers than current predictors such as anti-cyclic citrullinated peptide, radiographic damage early in the disease course, and signs of inflammation.

Serum IgG antibodies to peptidylarginine deiminase 4 in rheumatoid arthritis and associations with disease severity

Background: Antibodies targeting citrullinated antigens are specific for rheumatoid arthritis (RA). Citrullination is catalysed by the peptidylarginine deiminase (PAD) enzyme family. Critical enzymes are often targeted by disease-specific antibodies in complex immune-mediated diseases. Here, we have tested for autoantibodies against human recombinant PAD4 (hPAD4) in Caucasian RA patients. Methods: A time-resolved fluorometric immunoassay based on hPAD4 was developed to analyse sera from two RA cohorts (n = 237 and n = 177), one systemic lupus erythaematosus (SLE) cohort (n = 84) and 148 healthy controls. Simple and multiple analyses were performed to examine possible associations between anti-hPAD4 and disease variables. Results: Raised levels of anti-hPAD4 IgG were found in both RA cohorts compared to the controls, and 23% of the RA patients were anti-hPAD4 IgG positive. Anti-hPAD4 was associated with anti-cyclic citrullinated peptide (CCP) and rheumatoid factor (RF), as well as increased physical disability. Anti-hPAD4 was also associated with higher longitudinal radiographic damage scores and increased clinical joint pathology, but weaker than anti-CCP. No associations were found between anti-hPAD4 and selected Human leukocyte antigen (HLA)-DRB1 variants. Conclusions: Approximately 23% of Caucasian RA patients have serum IgG antibodies against hPAD4.The presence of serum anti-hPAD4 IgG was in simple analyses associated with a more severe disease phenotype, and the association with physical disability was maintained in multiple analyses.