Autoantibodies are major predictors of arthritis development in patients with anti-citrullinated protein antibodies and musculoskeletal pain.

Objectives: Predictors of arthritis development are highly warranted among patients with anti-citrullinated protein antibodies (ACPAs) and musculoskeletal symptoms to optimize clinical management. We aimed to identify clinical and laboratory predictors of arthritis development, including biochemically assessed alcohol consumption, among ACPA-positive patients with musculoskeletal pain.Method: 82 ACPA-positive individuals with musculoskeletal pain but no clinical arthritis were followed for a median of 72 months (interquartile range 57-81 months). We evaluated the prognostic value of baseline clinical and laboratory factors including smoking, symptom duration, age, gender, shared epitope, rheumatoid factor (RF), anti-carbamylated protein antibodies, ACPA levels, erythrocyte sedimentation rate, C-reactive protein levels, tender joint count, patient-reported general well-being, 28-joint Disease Activity Score, and alcohol consumption as measured by phosphatidyl ethanol (PEth) levels in whole blood.Results: During follow-up, 48% developed at least one arthritis. Multivariable analysis revealed an increased risk of arthritis development with RF positivity [hazard ratio (HR) = 2.3, 95% confidence interval (CI) 1.1-4.8, p = 0.028] and higher ACPA levels (HR = 1.0, 95% CI 1.000-1.001, p = 0.002). High levels of RF (HR = 4.4, 95% CI 1.7-11) entailed the highest HR in this ACPA-positive population. Neither clinical characteristics nor alcohol consumption measured by PEth conferred significant prognostic value.Conclusions: ACPA levels and concurrent presence of RF are independent predictors of arthritis development among ACPA-positive patients with musculoskeletal pain. The results are compatible with a dose-response relationship between RA-related autoantibodies and risk of arthritis development.

Anti-cyclic citrullinated peptide antibodies are associated with radiographic damage but not disease activity in early rheumatoid arthritis diagnosed in 2006-2011.

Objective: The discovery of anti-citrullinated protein antibodies (ACPAs) and the introduction of new therapeutic options have had profound impacts on early rheumatoid arthritis (RA) care. Since ACPA status, most widely assessed as reactivity to cyclic citrullinated peptides (CCPs), influences treatment decisions in early RA, we aimed to determine whether anti-CCP remains a predictor of disease activity and radiographic joint damage in more recent 'real-world' early RA. Method: Two observational early RA cohorts from Sweden enrolled patients in 1996-1999 (TIRA-1, n = 239) and 2006-2009 (TIRA-2, n = 444). Clinical and radiographic data and ongoing treatment were prospectively collected up to 3 years. Two other cohorts served as confirmation cohorts (TRAM-1, with enrolment 1996-2000, n = 249; and TRAM-2, 2006-2011, n = 528). Baseline anti-CCP status was related to disease activity, pharmacotherapy, and radiographic joint damage according to Larsen score. Results: In the TIRA-1 cohort, anti-CCP-positive patients had significantly higher 28-joint Disease Activity Score, swollen joint count, C-reactive protein level, and erythrocyte sedimentation rate during follow-up compared with anti-CCP-negative patients. In TIRA-2, no such differences were found, but baseline anti-CCP positivity was associated with higher 3 year Larsen score (5.4 vs 3.5, p = 0.039). In TRAM-2, anti-CCP also predicted radiographic damage (8.9 vs 6.7, p = 0.027), with no significant differences in disease activity. Conclusion: In the early RA cohorts recruiting patients in 2006-2011, baseline anti-CCP positivity was not associated with disease activity over time, but was associated with increased radiographic damage at follow-up. Hence, close radiographic monitoring is warranted in early anti-CCP-positive RA regardless of disease activity.

Longitudinal anti-nuclear antibody (ANA) seroconversion in systemic lupus erythematosus: a prospective study of Swedish cases with recent-onset disease.

Serum immunoglobulin (Ig)G anti-nuclear antibodies (ANA) detected by indirect immunofluorescence (IF) microscopy remains a hallmark of systemic lupus erythematosus (SLE). Whether or not IF-ANA status varies over time is controversial. We therefore designed a prospective study with longitudinal follow-up of patients with recent-onset SLE. The study population consisted of 54 recently diagnosed SLE cases, all meeting the 1982 American College of Rheumatology (ACR) and/or the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria. Clinical follow-up data, including disease activity, organ damage and sera, were collected from clinical onset of SLE and onwards, in most cases yearly (0-96 months). IF-ANA was analysed on human epithelial cells-2 (HEp-2) cells and categorized regarding staining patterns. Using an addressable laser bead assay (FIDIS™ Connective profile), we measured IgG-ANA fine specificities against Ro52/SSA, Ro60/SSA, Sjögren's syndrome type B antigen (La/SSB), Smith antigen (Sm), Smith antigen/ribonucleoprotein (Sm/RNP), U1 RNP (U1RNP), dsDNA, ribosomal-P protein and histone. At baseline, all patients were judged ANA-positive at an abnormal titre corresponding to the 95th percentile of healthy blood donors, but seven of 54 patients (13%) lost ANA-positivity over time. Homogeneous (AC-1; 46%) and speckled (AC-4 or 5; 31%) were the most frequently observed patterns at inclusion, whereas 7% switched pattern at least once during follow-up. Established associations between ANA fine specificities and clinical data were confirmed. Levels of anti-Sm/RNP, but not of anti-dsDNA, correlated with clinical disease activity [modified SLE disease activity 2000 (mSLEDAI-2K)]. Our data indicate that a considerable proportion of Swedish patients with SLE lose ANA-positivity over time, whereas consistent staining patterns were frequent. The clinical and mechanistic relevance of ANA seroconversion remains uncertain. Further prospective evaluations in larger SLE populations with more diverse ethnicities are warranted.

Immunoglobulin A anti-phospholipid antibodies in Swedish cases of systemic lupus erythematosus: associations with disease phenotypes, vascular events and damage accrual.

Immunoglobulin (Ig) G- and IgM-class anti-cardiolipin antibodies (aCL) and lupus anti-coagulant (LA) are included in the 1997 update of the American College of Rheumatology (ACR-97) systemic lupus erythematosus (SLE) criteria. Despite limited evidence, IgA-aCL and IgA anti-ß2 -glycoprotein-I (anti-ß2 GPI) were included in the 2012 Systemic Lupus International Collaborating Clinics criteria. The present study aimed to evaluate IgG-/IgA-/IgM-aCL and anti-ß2 GPI occurrence in relation to disease phenotype, smoking habits, pharmacotherapy, anti-phospholipid syndrome (APS) and organ damage among 526 Swedish SLE patients meeting ACR-97. Patients with rheumatoid arthritis (n = 100), primary Sjögren's syndrome (n = 50) and blood donors (n = 507) served as controls. Anti-phospholipid antibodies (aPL) were analysed by fluoroenzyme-immunoassays detecting aCL/anti-ß2 GPI. Seventy-six (14%) SLE cases fulfilled the Sydney APS-criteria, and ≥ 1 aCL/anti-ß2 GPI isotype (IgG/IgA/IgM) occurred in 138 SLE patients (26%). Forty-five (9%) of the SLE cases had IgA-aCL, 20 of whom (4%) lacked IgG-/IgM-aCL. Seventy-four (14%) tested positive for IgA anti-ß2 GPI, 34 (6%) being seronegative regarding IgG/IgM anti-ß2 GPI. Six (1%) had APS manifestations but were seropositive regarding IgA-aCL and/or IgA anti-ß2 GPI in the absence of IgG/IgM-aPL and LA. Positive LA and IgG-aPL tests were associated with most APS-related events and organ damage. Exclusive IgA anti-ß2 GPI occurrence associated inversely with Caucasian ethnicity [odds ratio (OR) = 0·21, 95% confidence interval (CI) = 0·06-0·72) and photosensitivity (OR = 0·19, 95% CI = 0·05-0·72). Nephritis, smoking, LA-positivity and statin/corticosteroid-medication associated strongly with organ damage, whereas hydroxychloroquine-medication was protective. In conclusion, IgA-aPL is not rare in SLE (16%) and IgA-aPL analysis may have additional value among SLE cases with suspected APS testing negative for other isotypes of aPL and LA.

Changes in anti-citrullinated protein antibody isotype levels in relation to disease activity and response to treatment in early rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease where serum analysis of anti-citrullinated peptide/protein antibodies (ACPA) is an important diagnostic/prognostic tool. Levels and changes of ACPA in RA patients have been studied previously in relation to disease course and therapy response, but less is known regarding ACPA isotype changes in early RA. Hence, recent-onset RA patients (n = 231) were subjected to a 3-year clinical and radiological follow-up. Serum samples were serially collected and ACPA isotypes were analysed using the second-generation cyclic citrullinated peptide (CCP) as capture antigen. Changes in ACPA isotype levels and status were related to disease course and pharmacotherapy. At inclusion, 74% of the patients tested positive for ACPA IgG; 55% for immunoglobulin (Ig)A, 37% for secretory IgA (SIgA) and 35% for IgM. The proportion of positive patients decreased significantly at follow-up regarding ACPA SIgA, IgM and IgA. During the initial 3 months, reduction of the 28-joint disease activity score (DAS28) correlated with reduced levels of ACPA IgG (Rho = 0·242, P = 0·003), IgA (Rho = 0·260, P = 0·008), IgM (Rho = 0·457, P < 0·001) and SIgA (Rho = 0·402, P < 0·001). Levels of ACPA SIgA (P = 0·008) and IgM (P = 0·021) decreased significantly among patients with good response to treatment, which was not seen regarding ACPA IgA or IgG. Changes in ACPA isotype levels were not associated with radiographic damage. In conclusion, ACPA SIgA and IgM declined rapidly upon anti-rheumatic therapy and correlated with decreased disease activity in recent-onset RA. This may indicate that down-regulation of mucosal immunity to citrullinated proteins/peptides and recruitment of new B cells are key features of therapy responses in early RA.

Interferon-α coincides with suppressed levels of pentraxin-3 (PTX3) in systemic lupus erythematosus and regulates leucocyte PTX3 in vitro.

Dysfunctional elimination of cell debris, and the role of opsonins such as pentraxins, is of interest regarding systemic lupus erythematosus (SLE) pathogenesis. Interferon (IFN)-α is typically elevated during SLE flares, and inhibits hepatocyte production of the pentraxin 'C-reactive protein' (CRP), partly explaining the poor correlation between CRP levels and SLE disease activity. The extrahepatically produced 'pentraxin 3' (PTX3) shares waste disposal functions with CRP, but has not been studied extensively in SLE. We analysed serum PTX3 in SLE, and assessed its interference with IFN-α in vitro. Serum samples from 243 patients with SLE and 100 blood donors were analysed regarding PTX3. Patient sera were analysed for IFN-α, and genotyped for three PTX3 single nucleotide polymorphisms reported previously to associate with PTX3 levels. Stimulated PTX3 release was assessed in the presence or absence of IFN-α in blood donor neutrophils and peripheral blood mononuclear cells (PBMC). Serum PTX3 was 44% lower in patients with SLE compared to blood donors (P < 0·0001) and correlated with leucocyte variables. Patients with undetectable IFN-α had 29% higher median PTX3 level than patients with detectable IFN-α (P = 0·01). PTX3 production by PBMC was inhibited by IFN-α, whereas neutrophil degranulation of PTX3 was increased. No differences in PTX3 levels were observed between the SNPs. In conclusion, median serum PTX3 is lower in SLE (especially when IFN-α is detectable) compared to blood donors. In addition to its potential consumption during waste disposal, it is plausible that IFN-α also attenuates PTX3 by inhibiting synthesis by PBMC and/or exhausting PTX3 storage in neutrophil granules.

Immunoglobulin (Ig)G1 and IgG4 anti-cyclic citrullinated peptide (CCP) associate with shared epitope, whereas IgG2 anti-CCP associates with smoking in patients with recent-onset rheumatoid arthritis (the Swedish TIRA project).

Given the possible importance of anti-citrullinated peptide/protein antibodies (ACPA) for initiation and progression of rheumatoid arthritis (RA), extended knowledge about the different isotypes and subclasses is important. In the present study, we analysed the immunoglobulin (Ig)G subclasses regarding reactivity against cyclic citrullinated peptides (anti-CCP) among 504 clinically well-characterized patients with recent-onset RA in relation to smoking habits, shared epitope (SE) status and IgA and pan-IgG anti-CCP antibodies. All patients, regardless of pan-IgG anti-CCP status, were analysed for IgG1-4 CCP reactivity. Sixty-nine per cent were positive in any IgG anti-CCP subclass, and of these 67% tested positive regarding IgG1, 35% IgG2, 32% IgG3, and 59% IgG4 anti-CCP. Among ever-smokers the percentages of IgG2 anti-CCP (P = 0·01) and IgA anti-CCP (P = 0·002)-positive cases were significantly higher compared to never-smokers. A positive IgG anti-CCP subclass -negative cases. Combining SE and smoking data revealed that IgG1 and IgG4 anti-CCP were the IgG anti-CCP isotypes associated with expression of SE, although the lower number of patients positive for IgG2 or IgG3 anti-CCP could, however, have influenced the results. High levels of IgG2 anti-CCP were shown to correlate with expression of the 'non-SE' allele human leucocyte antigen (HLA)-DRB1*15. In conclusion, in this study we describe different risk factor characteristics across the IgG anti-CCP subclasses, where IgG2 appears similar to IgA anti-CCP regarding the predominant association with smoking, while IgG1 and IgG4 related more distinctly to the carriage of SE genes.

Circulating cartilage oligomeric matrix protein in juvenile idiopathic arthritis.

OBJECTIVES: Raised serum cartilage oligomeric matrix protein (sCOMP) has been reported to predict erosive disease in early rheumatoid arthritis (RA). In juvenile idiopathic arthritis (JIA), subnormal sCOMP levels have been associated with ongoing inflammation and growth retardation. In this study we aimed to assess sCOMP, C-reactive protein (CRP), and insulin-like growth factor (IGF)-1 in children/adolescents with JIA and in referents. METHOD: We enrolled 52 JIA patients at planned outpatient visits and 54 inpatients with ongoing infection ('infection referents'). A total of 120 referents testing negative for immunoglobulin (Ig)E-mediated allergy ('IgE referents') served as controls. All serum samples were analysed for COMP, IGF-1, and CRP. RESULTS: The average sCOMP level was highest among the IgE referents and lowest among the infection referents. In the JIA patients, the level of sCOMP was not associated with the level of CRP or with clinical signs of disease activity. CONCLUSIONS: The results of this study do not support routine clinical analysis of sCOMP levels in patients with JIA.

IgA- and SIgA anti-PR3 antibodies in serum versus organ involvement and disease activity in PR3-ANCA-associated vasculitis.

Circulating immunoglobulin (Ig)A class anti-neutrophil cytoplasm antibodies (ANCA) directed against proteinase 3 (PR3) have been reported in ANCA-associated vasculitis (AAV) with mucosal involvement. However, secretory IgA (SIgA) PR3-ANCA has not been reported previously. In this study we compared serum levels of SIgA PR3-ANCA and IgA PR3-ANCA with IgG PR3-ANCA in relation to disease characteristics. Among 73 patients with AAV and PR3-ANCA at diagnosis, 84% tested positive for IgG PR3-ANCA, 47% for IgA-ANCA and 36% for SIgA PR3-ANCA at the time of sampling for the present study. IgA and IgG PR3-ANCA were represented similarly among patients with different organ manifestations, i.e. upper airway, lung or kidney at time of sampling. However, SIgA PR3-ANCA was significantly less represented among patients with upper airway involvement. During active disease, the proportions of IgA PR3-ANCA and SIgA PR3-ANCA-positive patients were significantly higher compared to inactive disease. Eight patients were sampled prospectively during 24 months from onset of active disease. In these patients, IgA PR3-ANCA and SIgA PR3-ANCA turned negative more often after remission induction compared to IgG PR3-ANCA. Our findings suggest that serum IgA PR3-ANCA and SIgA PR3-ANCA are related more closely to disease activity in AAV compared to IgG PR3-ANCA. Further studies are required to reveal if this has implications for disease activity monitoring. The mean number of PR3-ANCA isotypes increased along with disease activity, suggesting a global B cell activation during active disease.

Changes in sociodemographic characteristics at baseline in two Swedish cohorts of patients with early rheumatoid arthritis diagnosed 1996-98 and 2006-09.

OBJECTIVES: To compare baseline sociodemographic characteristics in two rheumatoid arthritis (RA) cohorts enrolled 10 years apart, and to examine differences with respect to the general population. METHOD: Clinical and sociodemographic data were collected in 320 early RA patients during 1996-98 (TIRA-1) and 467 patients in 2006-09 (TIRA-2). Multivariate logistic regression tests were performed and intercohort comparisons were related to general population data, obtained from official databases. RESULTS: TIRA-2 patients were older than TIRA-1 (58 vs. 56 years). Women (both cohorts, 67%) were younger than men in TIRA-1 (55 vs. 59 years) and in TIRA-2 (57 vs. 61 years). Disease activity was similar but TIRA-2 women scored worse pain and worse on the HAQ. Approximately 73% were cohabiting, in both cohorts and in the general population. Education was higher in TIRA-2 than in TIRA-2 but still lower than in the general population. Women had consistently higher education than men. Education was associated with age, younger patients having higher education. In both cohorts, lower education was associated with increased disability pension and increased sick leave. Sick leave was lower in TIRA-2 than in TIRA-1 (37% vs. 50%) but disability pension was higher (16% vs. 10%). In TIRA-1, 9% of women had disability pension compared with 17% in TIRA-2. A similar decrease in sick leave and an increase in disability pension were also seen in the general population. Older age and a higher HAQ score were associated with increased sick leave and being in the TIRA-2 cohort was associated with decreased sick leave. CONCLUSIONS: TIRA-2 patients were slightly older, better educated, had lower sick leave and higher disability pension than those in TIRA-1. Similar changes were seen simultaneously in the general population. Belonging to the TIRA-2 cohort was associated with decreased sick leave, indicating that societal changes are of importance.

Early rheumatoid arthritis 6 years after diagnosis is still associated with high direct costs and increasing loss of productivity: the Swedish TIRA project.

OBJECTIVES: To calculate total costs over 6 years after diagnosis of early rheumatoid arthritis (RA). METHOD: In the longitudinal prospective multicentre TIRA study, 239 patients from seven units, diagnosed in 1996-98, reported regularly on health-care utilization and the number of days lost from work. Costs were obtained from official databases and calculated using unit costs (Swedish kronor, SEK) from 2001. Indirect costs were calculated using the human capital approach (HCA). Costs were inflation adjusted to Euro June 2012, using the Swedish Consumer Price Index and the exchange rate of June 2012. Statistical analyses were based on linear mixed models (LMMs) for changes over time. RESULTS: The mean total cost per patient was EUR 14,768 in year 1, increasing to EUR 18,438 in year 6. Outpatient visits and hospitalization decreased but costs for surgery increased from EUR 92/patient in year 1 to EUR 444/patient in year 6. Drug costs increased from EUR 429/patient to EUR 2214/patient, mainly because of the introduction of biologics. In year 1, drugs made up for 10% of direct costs, and increased to 49% in year 6. Sick leave decreased during the first years but disability pensions increased, resulting in unchanged indirect costs. Over the following years, disability pensions increased further and indirect costs increased from EUR 10,284 in year 1 to EUR 13,874 in year 6. LMM analyses showed that indirect costs were unchanged whereas direct costs, after an initial fall, increased over the following years, leading to increasing total costs. CONCLUSIONS: In the 6 years after diagnosis of early RA, drug costs were partially offset by decreasing outpatient visits but indirect costs remained unchanged and total costs increased.

IgG rheumatoid factors against the four human Fc-gamma subclasses in early rheumatoid arthritis (the Swedish TIRA project).

Rheumatoid factor (RF), i.e. a family of autoantibodies against the Fc part of IgG, is an important seromarker of rheumatoid arthritis (RA). Traditional particle agglutination without disclosing the antibody isotype remains the predominating diagnostic method in clinical routine. Although IgG-RF attracts pathogenic interest, its detection remains technically challenging. The present study aimed at developing a set of tests identifying IgG-RFs directed against the four IgG subclasses. IgG-RF against either subclass of human IgG-Fc were analysed with four novel enzyme-linked immunosorbent assays (ELISAs) utilizing four recombinant human Fc-gamma fragments (hIgG1-4) as sources of antigen. Sera from 40 patients with recent onset RA (20 seropositive and 20 seronegative by IgM-RF and IgA-RF-isotype-specific ELISA) were analysed. Sera from 20 healthy blood donors served as reference. Among the IgM-/IgA-RF-positive RA-sera, IgG-RF was found directed against hIgG1 and hIgG2, but not against hIgG3 or hIgG4. Significant correlations were seen between IgG-RF against hIgG2-Fc and IgM-RF (r = 0.666) levels. Further prospective studies are warranted to elucidate any correlation to disease course and outcome.

A population-based investigation of the autoantibody profile in mothers of children with atrioventricular block.

The objective of the study was to investigate the antigen specificity and occurrence of individual autoantibodies in mothers of children diagnosed with atrioventricular (AV) block in a nation-wide setting. Patients with AV block detected before 15 years of age were identified using national quality registries as well as a network of pediatric and adult cardiologists and rheumatologists at the six university hospitals in Sweden. Patients with gross heart malformations, surgically or infectiously induced blocks were excluded. Blood samples were obtained from the mothers and maternal autoantibody profile, including the occurrence of antibodies against Ro52, Ro60, La, SmB, SmD, RNP-70k, RNP-A, RNP-C, CENP-C, Scl-70, Jo-1, ribosomal RNP and histones was investigated in 193 mothers of children with AV block by immunoblotting and ELISA. Autoantibody reactivity was detected in 48% (93/193) of the mothers of children with AV block. In autoantibody-positive mothers, the vast majority, 95% (88/93), had antibodies against Ro52, while 63% (59/93) had autoantibodies to Ro60 and 58% (54/93) had autoantibodies to La. In addition, 13% (12/93) of the autoantibody-positive mothers had antibodies to other investigated antigens besides Ro52, Ro60 and La, and of these anti-histone antibodies were most commonly represented, detected in 8% (7/93) of the mothers. In conclusion, this Swedish population-based study confirms that maternal autoantibodies may associate with heart block in the child. Further, our data demonstrate a dominant role of Ro52 antibodies in association with AV block.

Improved outcome in Wegener's granulomatosis and microscopic polyangiitis? A retrospective analysis of 95 cases in two cohorts.

OBJECTIVES: Mortality rates for Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) have decreased after the introduction of cyclophosphamide. Standardized mortality ratio (SMR) expresses the overall mortality of patients compared with the general population. The aims of this study were to compare survival in an old and a recent cohort of patients with WG and MPA using SMR and to determine predictors for death in both groups combined. DESIGN: Survival analyses were performed by Kaplan-Meier survival curves, SMR and proportional hazards regression models. SETTING: The nephrology and rheumatology clinics at Linköping University Hospital, Sweden. SUBJECTS: All patients diagnosed with WG or MPA in the catchment area during 1978-2005 were divided into two cohorts; patients diagnosed before (n=32, old cohort) and after (n=63, recent cohort) December 31, 1996. RESULTS: The two cohorts differed regarding the proportion of WG (75% vs. 56%, P=0.03) and a tendency for more pronounced kidney involvement in the old cohort: 266 micromol L(-1) (16% dialysis-dependent) vs. 192 micromol L(-1) (5% dialysis-dependent), but were comparable regarding disease severity. SMR at 1 and 5 years were 2.1 (95% CI: 0.43-6.09) and 1.6 (95% CI: 0.6-3.2) in the recent cohort and 5.2 (95% CI: 1.07-15.14) and 2.5 (95% CI: 0.93-5.52) in the old cohort. Five-year survival was 87% and 81%. Serum creatinine, age, end-stage renal disease, diagnosis before 1997 and first relapse were independent predictors for death. CONCLUSION: Patient survival in WG and MPA analysed with SMR may be better than previously believed. Severe renal disease and disease relapse were the major predictors of reduced survival.

Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (the Swedish TIRA project).

OBJECTIVES: The genetic background to RA is incompletely understood. As new cytokine-targeted therapies emerge, early predictors of disease severity are becoming increasingly important. The inflammasomes are essential regulators of cytokine production. We investigated whether two polymorphisms in the genes encoding cryopyrin (CIAS1) and TUCAN (CARD8) influence susceptibility and disease course in RA. METHODS: Genotype frequencies were assessed in 174 Swedish patients with early RA and 360 population-based controls without rheumatic disease. Genotypes were categorized according to the presence (+) or absence (-) of two wild-type alleles and compared between patients and controls. In the RA patients, antibodies towards cyclic citrullinated peptides (anti-CCP) and the 'shared epitope' (SE) were assessed, and medication and measures of disease activity were monitored regularly during 3 yrs. RESULTS: The combination of CIAS1/TUCAN -/-, as compared with CIAS1/TUCAN +/+, was significantly more common among patients than in controls [odds ratio (OR) 2.2, 95% CI 1.03-4.6]. This association was strengthened when patients were divided into anti-CCP+ [OR 2.8 (1.1-6.7)] or presence of > or = 1 SE copy [OR 2.8 (1.3-6.2)]. At most time-points during the 3-yr follow-up, patients with CIAS1/TUCAN -/- showed significantly higher disease activity. Furthermore, CIAS1/TUCAN -/- patients proved to be much more likely to receive TNF-blocking therapy [relative risk 20 (2.6-149)]. CONCLUSIONS: Compound polymorphisms in CIAS1 and TUCAN associate with RA susceptibility and severity. The cryopyrin inflammasome needs further attention regarding a possible aetiopathogenetic connection with RA.

Cytokine induction by circulating immune complexes and signs of in-vivo complement activation in systemic lupus erythematosus are associated with the occurrence of anti-Sjögren's syndrome A antibodies.

Circulating immune complexes (IC) and levels of IC-induced cytokines have been correlated with complement activation and autoantibody profiles in systemic lupus erythematosus (SLE). SLE sera were analysed concerning levels of immune complexes (IC), classical complement function and different antinuclear and anti-C-reactive protein (CRP) autoantibodies. Blood mononuclear cells from healthy donors were stimulated with isolated IC and production of interleukin (IL)-10, IL-6 and IL-12p40 was measured. Functional experiments revealed that increased levels of IC-induced cytokines were associated with both increased classical complement activation and the occurrence of anti-Sjögren's syndrome A (SSA) and anti-SSB but not other autoantibodies. Biochemical measurement of circulating IC showed that the degree of complement activation and the occurrence of anti-SSA were synergistically associated with levels of circulating IC in SLE sera, as complement activation was a prerequisite for the enhancing effect of anti-SSA. Anti-CRP was associated with complement activation, but not with other autoantibodies. Our results indicate that anti-SSA and possibly anti-SSB antibodies influence IC formation and subsequent IC-induced cytokine induction, and that they thereby participate in the inflammatory process in active SLE.

Hand function in women and men with early rheumatoid arthritis. A prospective study over three years (the Swedish TIRA project).

OBJECTIVE: To describe the course of hand function in women and men during the first 3 years after diagnosis of recent-onset rheumatoid arthritis (RA), to investigate sex differences in hand function, and to study correlations between and within hand function assessments. METHODS: A total of 276 patients (69% women) with RA of a maximal duration of 12 months were recruited to the study. Hand function was assessed by the Grip Ability Test (GAT) and Signals of Functional Impairment (SOFI). Peak and average grip force over 10 s in the right and left hand was measured by an electronic device. RESULTS: Hand function was affected at diagnosis, but had improved significantly at the 3-months' follow-up and then remained stable (but still affected) in both women and men. As assessed by SOFI, hand function was worse in men than in women, whereas women had significantly lower grip force. GAT, grip force, and SOFI correlated weakly. The average and peak values of grip force correlated strongly, as did the grip force in the right and the left hand. CONCLUSION: Hand function was profoundly affected at diagnosis of RA, but improved significantly within 3 months and remained stable (but still affected) over 3 years. As expected, women on average had significantly lower grip force than men.

Costs and course of disease and function in early rheumatoid arthritis: a 3-year follow-up (the Swedish TIRA project).

OBJECTIVE: To calculate direct and indirect costs and to study disease activity and functional ability over 3 yr in early rheumatoid arthritis (RA). METHODS: Three hundred and three patients with early (< or = 1 yr) RA were recruited during a period of 27 months (1996-1998). Data were recorded during 3 yr to assess disease activity, functional ability, medication, health-care utilization and days lost from work. RESULTS: Within 3 months, improvements were seen regarding all recorded variables assessing disease activity and functional ability, but 15% had sustained high or moderate disease activity throughout the study period. Indirect costs exceeded direct costs in all 3 yr. The average direct costs were 3704 Euros (3297 US Dollars) in year 1 and 2652 Euros ( 2360 US Dollars ) in year 3. All costs decreased, except those for medication and surgery. Compared with men, women had more ambulatory care visits and used more complementary medicine. The indirect costs were 8871 Euros ( 7895 US Dollars) in year 1 and remained essentially unchanged; this was similar for both sexes. Almost 50% were on sick leave or early retirement at inclusion. Sick leave decreased but was offset by an increase in early retirement. The 14 patients who eventually received TNF inhibitors incurred higher costs even before prescription of anti-TNF therapy. CONCLUSION: Disease activity and functional ability improved within 3 months after diagnosis of early RA. Direct costs decreased, except for medication and surgery. Indirect costs remained unchanged. Fifteen per cent of the patients had high or moderate disease activity in all 3 yr, indicating a need for more aggressive early anti-rheumatic therapy.

The 158V polymorphism of Fc gamma receptor type IIIA in early rheumatoid arthritis: increased susceptibility and severity in male patients (the Swedish TIRA project).

OBJECTIVES: To evaluate the influence of Fcgamma receptor IIIA (FcgammaRIIIA) 158V/F polymorphism on susceptibility and disease severity in early rheumatoid arthritis (RA). METHODS: In 181 Swedish patients (128 women, 53 men) with RA of recent onset, disease and disability variables such as erythrocyte sedimentation rate, 28-joint disease activity score (DAS28) and health assessment questionnaire (HAQ) scores were monitored regularly during 3 yr. Three hundred and sixty-two controls were recruited from the same geographical area as the patients. FcgammaRIIIA genotyping was performed using denaturing high-performance liquid chromatography. RESULTS: In all RA patients, FcgammaRIIIA-158VV was significantly over-represented compared with controls [odds ratio (OR) 1.9, 95% confidence interval (CI) 1.01-3.5, P<0.05]. After stratifying for sex, the difference remained in the male population (OR 3.2, 95%CI 1.03-11, P<0.05) but disappeared among women (OR 1.4, 95%CI 0.7-3.1, P=0.4). In addition, 158VV patients were more likely to exhibit early joint erosions (OR 6.1, 95%CI 1.4-28, P<0.01). At baseline, patients with different FcgammaRIIIA genotypes did not differ with respect to measures of disease activity or functional ability. Thereafter, in male patients with at least one V allele the mean DAS28 and HAQ scores were higher compared with 158FF. In contrast, female patients with at least one 158V allele displayed lower mean DAS28 and HAQ scores compared with those with 158FF. CONCLUSIONS: In a male population, the FcgammaRIIIA-158VV genotype is associated with an increased risk of developing RA, and the 158V allele with more severe disease in early RA.

Aetiological factors of importance for the development of rheumatoid arthritis.

OBJECTIVE: To evaluate exposure to external factors associated with risk or prevention of rheumatoid arthritis (RA). METHODS: Two hundred and ninety-three incident cases of RA and 1346 population-based referents were included in a case-referent study, in which previous exposure experiences were collected through a postal questionnaire. RESULTS: An inverse association between RA and additional schooling after compulsory school was seen for men. Current smoking was associated with significantly increased risks of RA for men and women [odds ratio (OR) 2.9, 95% confidence interval (CI) 1.4-6.4, and OR 1.8, 95% CI 1.1-2.9, respectively], as was previous smoking for men (OR 2.3, 95% CI 1.2-4.4). There were also indications of relationships between previous use of a private well and RA in both men and women. CONCLUSION: Several previously published associations have been reproduced in the present study, which also generates some new hypotheses that suggest further research.