Anna Svärd

Presence and utility of IgA-class antibodies to cyclic citrullinated peptides in early rheumatoid arthritis: the Swedish TIRA project

IntroductionThe present study was carried out to assess whether IgA-class antibodies against cyclic citrullinated peptides (IgA anti-CCP) in recent-onset rheumatoid arthritis add diagnostic and/or prognostic information to IgG anti-CCP analysis.MethodsSerum samples were obtained from 228 patients with recent-onset (<12 months) rheumatoid arthritis at the time of inclusion in the Swedish TIRA cohort (Swedish Early Intervention in Rheumatoid Arthritis). Sera from 72 of these patients were also available at the 3-year follow-up. Disease activity and functional ability measures (erythrocyte sedimentation rate, serum C-reactive protein, 28-joint count Disease Activity Score, physicians assessment of disease activity, and the Swedish version of the Health Assessment Questionnaire) were registered at inclusion and at regular follow-ups during 3 years. An IgA anti-CCP assay was developed based on the commercially available IgG-specific enzyme immunoassay from EuroDiagnostica (Arnhem, the Netherlands), replacing the detection antibody by an anti-human-IgA antibody. A positive IgA anti-CCP test was defined by the 99th percentile among healthy blood donors.ResultsAt baseline, a positive IgA anti-CCP test was observed in 29% of the patient sera, all of which also tested positive for IgG anti-CCP at a higher average level than sera containing IgG anti-CCP alone. The IgA anti-CCP-positive patients had significantly higher disease activity over time compared with the IgA anti-CCP-negative patients. After considering the IgG anti-CCP level, the disease activity also tended to be higher in the IgA anti-CCP-positive cases – although this difference did not reach statistical significance. The proportion of IgA anti-CCP-positive patients was significantly larger among smokers than among nonsmokers.ConclusionAnti-CCP antibodies of the IgA class were found in about one-third of patients with recent-onset rheumatoid arthritis, all of whom also had IgG anti-CCP. The occurrence of IgA-class antibodies was associated with smoking, and IgA anti-CCP-positive patients had a more severe disease course over 3 years compared with IgA anti-CCP-negative cases. Although IgA anti-CCP analysis does not seem to offer any diagnostic information in addition to IgG anti-CCP analysis, further efforts are justified to investigate the prognostic implications.

A Comparison Between IgG- and IgA-class Antibodies to Cyclic Citrullinated Peptides and to Modified Citrullinated Vimentin in Early Rheumatoid Arthritis and Very Early Arthritis

Objective. Because of their slightly higher sensitivity, it has been argued that antibodies to modified citrullinated vimentin (anti-MCV) are superior to antibodies to cyclic citrullinated peptides (anti-CCP), while others claim that anti-CCP is preferable because of higher diagnostic specificity for rheumatoid arthritis (RA). We evaluated IgG- and IgA-class anti-MCV and anti-CCP as diagnostic and prognostic markers in early arthritis. Methods. Two Swedish arthritis populations were examined: 215 patients with early RA (≤ 12 months’ duration) from the Swedish TIRA-1 cohort, and 69 patients with very early arthritis (≤ 3 months’ duration) from the Kronoberg Arthritis Incidence cohort, in which 22% were diagnosed with RA. IgG anti-CCP and anti-MCV antibodies were analyzed with commercial kits. These tests were modified for IgA-class antibody detection. Results were related to disease course, smoking habits, and shared epitope status. Results. In the TIRA-1 cohort, occurrence of IgG anti-MCV and IgG anti-CCP showed a 93% overlap, although IgG anti-MCV had higher diagnostic sensitivity. Twenty-four percent tested positive for IgA anti-MCV compared to 29% for IgA anti-CCP. In the Kronoberg Arthritis Incidence cohort, 15% tested positive for IgG anti-MCV and 6% for IgA anti-MCV, compared to 10% positive for IgG anti-CCP and 3% positive for IgA anti-CCP, revealing that anti-CCP had higher diagnostic specificity for RA. As previously reported for IgA anti-CCP, IgA anti-MCV antibodies occurred in a small proportion of high-level IgG antibody-positive sera and were associated with a more aggressive disease course. Smokers were more often positive for antibodies to citrullinated proteins, most strikingly among the patients who were IgA anti-MCV-positive. Conclusion. The occurrences of IgG-class anti-MCV and anti-CCP in early RA largely overlap. The sensitivity of anti-MCV is slightly higher, while the diagnostic specificity is higher for anti-CCP. In both instances a positive test predicts an unfavorable disease course, possibly slightly more so for anti-MCV. Although associated with a more active disease over time, IgA-class anti-CCP or anti-MCV do not add any diagnostic advantage.

Associations With Smoking and Shared Epitope Differ Between IgA‐ and IgG‐Class Antibodies to Cyclic Citrullinated Peptides in Early Rheumatoid Arthritis

Smoking and HLA–DRB1/shared epitope (SE) alleles are risk factors for rheumatoid arthritis (RA) characterized by seropositivity for antibodies targeting citrullinated proteins (ACPAs)/cyclic citrullinated peptides (anti‐CCP). Previously, mainly IgG‐class antibodies have been studied. IgA‐class antibodies are to a great extent related to mucosal immunity. The aim of this study was to explore interrelations between cigarette smoking, presence of SE, and seropositivity for circulating IgA and/or IgG anti‐CCP antibodies among patients with early RA, to determine whether ACPAs of the IgA subclass are regulated by different mechanisms than those of the IgG subclass.

Salivary IgA antibodies to cyclic citrullinated peptides (CCP) in rheumatoid arthritis

Circulating IgG anti-cyclic citrullinated peptide antibodies (CCP) are highly specific for rheumatoid arthritis (RA) and prognostic of poor outcome. Serum IgA anti-CCP occurs in a subset of IgG-positive cases and relates to still more aggressive disease. Mucosal IgA-class antibodies, however, are generally associated with anti-inflammatory actions and systemic tolerance induction. In the present study, unstimulated salivary samples from 63 patients with established RA and 20 healthy persons were analysed by enzyme-linked immunoassay for the presence of IgA anti-CCP antibodies. To ensure antigen specificity, IgA-reactivity with the corresponding uncitrullinated antigen, cyclic arginine peptide (CAP), was analysed and anti-CCP/anti-CAP ratios calculated. Retrospective data regarding disease activity and radiological outcome were achieved via medical records. Salivary IgA anti-CCP was found in 14/63 (22%) patients and one (5%) control (positive test=anti-CCP/anti-CAP ratio>1.5). Salivary IgA reactivity was dose-dependently inhibited by pre-incubation with soluble CCP to a degree strongly correlating with anti-CCP/anti-CAP ratio. In salivary IgA anti-CCP positive patients, joint erosions within 6 years of diagnosis was significantly lower (p=0.043), and at the time for diagnosis there was a trend towards lower erythrocyte sedimentation rate (p=0.071) and C-reactive protein (p=0.085). Contrasting to circulating IgG and IgA anti-CCP, our results imply that salivary IgA antibodies may be associated with a less severe outcome of RA. Hypothetically, this relates to an anti-inflammatory and protective immunomodulating role of secretory IgA-class autoantibodies against citrullinated antigens presented at mucosal surfaces.

Altered glycan accessibility on native immunoglobulin G complexes in early rheumatoid arthritis and its changes during therapy

The goal of this study was to investigate the glycosylation profile of native immunoglobulin (Ig)G present in serum immune complexes in patients with rheumatoid arthritis (RA). To accomplish this, lectin binding assays, detecting the accessibility of glycans present on IgG‐containing immune complexes by biotinylated lectins, were employed. Lectins capturing fucosyl residues (AAL), fucosylated tri‐mannose N‐glycan core sites (LCA), terminal sialic acid residues (SNA) and O‐glycosidically linked galactose/N‐acetylgalactosamine (GalNac‐L) were used. Patients with recent‐onset RA at baseline and after 3‐year follow‐up were investigated. We found that native IgG was complexed significantly more often with IgM, C1q, C3c and C‐reactive protein (CRP) in RA patients, suggesting alterations of the native structure of IgG. The total accessibility of fucose residues on captured immune complexes to the respective lectin was significantly higher in patients with RA. Moreover, fucose accessibility on IgG‐containing immune complexes correlated positively with the levels of antibodies to cyclic citrullinated peptides (anti‐CCP). We also observed a significantly higher accessibility to sialic acid residues and galactose/GalNAc glyco‐epitopes in native complexed IgG of patients with RA at baseline. While sialic acid accessibility increased during treatment, the accessibility of galactose/GalNAc decreased. Hence, successful treatment of RA was associated with an increase in the SNA/GalNAc‐L ratio. Interestingly, the SNA/GalNAc‐L ratio in particular rises after glucocorticoid treatment. In summary, this study shows the exposure of glycans in native complexed IgG of patients with early RA, revealing particular glycosylation patterns and its changes following pharmaceutical treatment.

Work disability in gout: a population-based case–control study

Objectives To examine the extent and cost of work disability among patients with gout compared with matched population controls and to analyse predictors of work disability. Methods A regional cohort study using data from Swedish national and regional registries from January 2000 through December 2012, including 4571 patients with gout of working age, with a first recorded diagnosis of gout in the years 2003–2009 and 22 482 population controls, matched by age, sex and place of residence. Differences in baseline characteristics (educational level, income, previous employment and comorbidities) and the number of work-loss days (absenteeism) due to sick leave and disability pension for 3 years after identification were calculated. Predictors for new-onset work absenteeism (>90 days/year) in a subset were determined by conditional logistic regression. Results Patients with gout (median age 53 years) had significantly more comorbidities, lower income and lower level of education than matched controls. The average work absentee rate during the 3-year follow-up period was higher among patients with gout than controls, 22% and 14%, respectively (P<0.0001). New-onset absenteeism was in multivariate analyses significantly predicted by gout (OR 1.47; 95% CI 1.23 to 1.75). Other variables independently related to new-onset absenteeism were education ≤12 years, previous unemployment and history of sick leave, in addition to several comorbidities (renal disease, cardiovascular disease, alcohol abuse and obesity). Conclusions Gout is associated with substantially higher work absenteeism and costs for society due to productivity loss, after adjusting for associated comorbidities and socioeconomic differences. Whether more intensive treatment of gout is cost-effective needs to be addressed in future studies.

OP0262 Trends and costs for gout hospitalization in sweden

Background Gout is the most common arthritic disease in the world with increasing incidence and prevalence. There are differences in gout prevalence and course of disease due to cultural, ethnical and genetic factors stressing the need for data from different parts of the world. An increase in hospitalization for gout has been shown for the last two decades in North America. Objectives We evaluated the trend for hospitalization of gout in western Sweden 2000 – 2012 and the health care costs for this 2009 – 2012. Methods Hospitalization trends for gout were studied using data from the health care consumption register in the Western Swedish Health Care Region (WSHCR) from 2000–01–01 through 2012–12–31. This area is considered to be representative for the country as a whole. Patients aged 18 years and older who were hospitalized during the study period with a principal ICD-10 diagnosis of gout (M10) at discharge were included. We calculated annual population rates for hospitalization for gout. Inflation-adjusted health care costs for the gout hospitalizations were calculated using the Cost-Per-Patient register (CPP). Dispensation of urate lowering therapy (ULT), allopurinol (M04AA01) and probenecid (M04AB01), within 6 months prior to hospitalization was identified using The Swedish Prescribed Drug Register. Results There were 1873 hospitalizations for gout (mean age 75.0–77.6 years, 61–74% men) between 2000 and 2012. Demographic characteristics were similar over the study period. From 2000 to 2012, the annual hospitalization rate for gout increased from 12.2 to 16.7 per 100 000 adults (p=0.0038). The increase was most pronounced in males aged 65 and above and over the last three years of the study. From 2009 to 2012 the inflation-adjusted health care costs for gout hospitalizations increased from 5.21 to 8.15 105 USD. The duration of hospitalizations also increased from 3 to 5 days median 2000 and 2012 respectively (p=0.021). Only a minority of patients, 19 to 27%, received ULT the 6 months preceding their hospitalization, without any obvious secular trend.Table 1 2000 2002 2004 2006 2008 2009 2010 2011 2012 Discharges, no 142 112 108 133 140 144 187 180 213 Incidence per 100 000 adults 12.2 9.5 9. 1 11.0 11.3 11.5 14.9 14.2 16.7 Men, incidence per 100 000 adults 16.1 12.3 12.9 14.4 15.7 16.0 22.0 21.1 24.3 Women, incidence per 100 000 adults 8.4 6.8 5.3 7.7 7.0 7.1 7.9 7.3 9.1 Duration, days, median (range) 3 (1–71) 3 (1–44) 5 (1–75) 5 (1–65) 5 (1–40) 5 (1–39) 5 (1–34) 5 (1–52) 5 (1–41) Age, years, mean, SD 76.2 (12.1) 74.3 (14.9) 76.3 (11.7) 77.2 (10.2) 77.4 (11.4) 76.7 (11.6) 77.6 (12.7) 75.6 (14.1) 75.0 (13.8)  18–44 3 6 1 0 5 4 8 8 4  45–64 23 16 17 19 12 11 19 28 41  65–84 83 63 67 80 85 89 100 92 108  ≥85 33 27 23 34 38 40 60 52 60 ULT, (%), 6 months before hospitalization 28 (21) 38 (27) 27 (19) 38 (20) 47 (26) 45 (21) Total cost*, 105 USD 5.21 6.8 6.6 8.15 Conclusions Incidence of hospitalization for primary gout is increasing substantially in Sweden over the last decade and this is reflected in the health care costs. The main part of this increase consists of males aged 65 and above. Only a fourth of the patients were on ULT preceding the hospitalization. These findings are further emphasized by the fact that the total amount of days for somatic inpatient care in WSHCR decreased by 9% from 2002 (1 267 900 days, mean duration 5,7 days) to 2012 (1 151 630 days, mean duration 4,9 days). The findings in this study reflects increasing incidence of the gout disease and an ageing population but also a considerable lack of treatment. Disclosure of Interest None declared

AB0831 Low Education Level as A Predictor of Gout in Western Sweden: Table 1.

Background Gout was previously regarded a disease of the affluent. Knowledge about the association between gout and socioeconomic status in modern times is limited. Objectives To investigate the association between gout and socioeconomic factors in a population based register study in a large region in Sweden. Methods All patients receiving ≥2 diagnoses of gout on at least two separate occasions in primary or secondary care or 1 diagnosis by a specialist in Rheumatology in Västra Götaland in the years 2007–2012 were identified by ICD10 codes in a regional database of health-care utilization. 3189 such patients were identified. The date of the first diagnosis was defined as the index date. A previous validation study of cases identified in this manner confirmed that this case definition is highly consistent with a diagnosis of gout as defined by established criteria (PPV >80%)(1). For each case, up to 5 controls matched for age, gender and place of residence at the time of the first gout diagnosis were chosen by the Statistics Sweden agency (SCB) (N=14946). Common comorbidities known to be associated with gout (ischemic heart disease, heart failure, atrial fibrillation, hypertension, hyperlipidemia, diabetes and renal failure) prior to the index date were retrieved from the regional database of health-care utilization based on ICD10-codes. Data on education level and income at the index year was collected from the Longitudinal Integration Database for health Insurance and Labor market studies (LISA). The database holds annual registers since 1990 on all individuals above 16 years of age registered in Sweden. Results Data on education level and income was analyzed for cases and controls belonging to the working-age population as defined in Sweden (aged 15–74 years). Shorter education, <12 years, was significantly more common among cases. Yearly income was lower among cases irrespective of educational length (Table 1). Cases had significantly more pre-index comorbidities compared to the controls. In a subgroup analysis of 1084 cases and 6117 controls of working age without any cardiovascular- or renal comorbidity, educational level and income was still significantly lower among cases (data not shown).Table 1. Education and income for individuals aged 15–74 years Educational length in years Mean yearly income in EUR Cases, N (%) Controls, N (%) p-value Cases Controls p-value ≥12 406 (20) 2730 (28) <0.001 22830 26230 0.037 <12 1598 (79) 6961 (71) 11850 12930 0.021 *1% of cases and controls had missing info on educational length. Conclusions Low education level and income are predictors for gout in the working age population. The effects of education do not seem to be largely/only mediated via cardiovascular- or renal comorbidity, supporting that other factors possibly related to lifestyle or occupational exposures are of importance for gout development. References Dehlin M, Stasinopoulou K, Jacobsson L. Validity of gout diagnosis in Swedish primary and secondary care – a validation study. BMC Musculoskelet Disord. 2015;16:149. Disclosure of Interest None declared

THU0522 Increasing Incidence of Gout in Western Sweden – A Register Study

Background Gout is the most common inflammatory arthritic disease worldwide. The prevalence varies due to cultural, ethnical and genetic differences in populations, which emphasizes the need for national/regional data on occurrence. While there are several studies on the prevalence of gout only few have addressed the incidence of gout and there are no contemporary studies in Sweden and the neighbouring Nordic countries. Objectives In the present study we measured the incidence of gout in 2012 and its trends from 2004 to 2012 in the Western Swedish Health Care Region (WSHCR) in Sweden. Methods We identified all incident cases of gout from 2004 through 2012 through VEGA, a diagnosis register covering all visits to physicians in primary and secondary care and hospitalizations in WSHCR. WSHCR has 1 600 000 inhabitants, roughly 20% of the population of Sweden, and is representative for the country as a whole with regard to demographics and health status. For the analyses of incidence trends an incident case of gout was defined as having a visit with a first ICD-10 diagnosis of gout (M10, M14) not preceded by a diagnosis of gout for the three calendar years before. Cumulative incidence per year was calculated using the number of incident gout cases aged 20 and above by calendar year (from 2004 to 2012) as the numerator and the total person-years aged 20 and above of WSHCR by the end of each year as the denominator. We calculated standardized estimates (direct method) using the whole Swedish population aged ≥20 years in 2012 as standard population Calculation of incidence trend was performed using logistic regression. Incidence in 2012 was based on cases with their first diagnosis of gout 2012 without any such diagnosis during the12 preceding years (2000–2011). All cases were linked to Statistics Sweden (for death and possible emigration before Dec 2012). Results The incidence of gout increased steadily and significantly (p for trend <0.001) from 2004 to 2012 with a 50% increase in the total population. The male to female ratio of gout incidence was consistently two to three fold from 2004 to 2012 (Fig. 1). The incidence of gout in Sweden 2012 was 190 cases per 100 000 person-years. Conclusions Gout is an increasing health care problem all over the world and also in western Sweden where the incidence of gout increased significantly over the last decade being approximately three times higher than that for rheumatoid arthritis. This increase might reflect changes in the disease panoramic and cultural changes. Disclosure of Interest None declared

THU0521 Prevalence of Gout and ULT Treatment in Western Sweden – A Register Study

Background Gout is the most common inflammatory arthritic disease worldwide. The prevalence varies due to cultural, ethnical and genetic differences in populations, which emphasizes the need for national/regional data on occurrence. There are major insights in the pathogenesis and effective treatments have been available for decades. Despite this several earlier reports state sub-optimal treatment with urate lowering therapy (ULT) of this common and severe disease. Contemporary data on whether this has improved recently are overall few and completely lacking from the Nordic countries. Objectives In the present study we measured the prevalence of gout in western Sweden and the proportion thereof treated with ULT. Methods We identified all individuals with one or more ICD-10 diagnosis of gout (M10, M14) in the Western Swedish Health Care Region (WSHCR), Sweden, 2002-01-01 to 2012-12-31 through VEGA, a diagnosis register entailing all visits to physicians in primary and secondary care and hospitalizations in the region with diagnosis according to the Swedish version of ICD-10. WSHCR has 1 600 000 inhabitants, roughly 20% of the population of Sweden and is representative for the country as a whole with regard to demographics and health status. All cases were linked to Statistics Sweden (for death and possible emigration before Dec 2012) and the National Drug Prescription Register (for dispensation of ULT prescriptions during 2012). The point prevalence of gout Dec 2012 was calculated using the number of people aged 20 and above fulfilling our case definitions for gout who were alive and living in WSHCR 2012-12-31 as the numerator and the total population aged 20 and above of WSHCR by 2012–12–31 as the denominator. Dispensation of ULT prescriptions during 2012 were identified for allopurinol, febuxostat and probenecid. The presence of ≥1 dispensation was regarded as ULT treatment in 2012. Results The prevalence of gout in the Swedish population aged 20 years and above was 1,7% overall and increased with age and male sex (Fig 1), and was more than 3% in males above 50 years of age. Only 43% of the patients received treatment with ULT in 2012, almost exclusively allopurinol (99%). Of these 43%, the majority (59%) received a dose of only 100 mg allopurinol daily. Conclusions Gout is the most common inflammatory arthritic disease in Sweden with an overall prevalence of 1.7%. Treatment with ULT is still in 2012 insufficient with low a low proportion being treated and those treated receiving low doses. Disclosure of Interest None declared