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Objective: The aim of the study was to analyse associations between anti-inflammatory treatment before a first acute myocardial infarction (AMI) and survival up to 365 days post-AMI in patients with and without rheumatoid arthritis (RA).

Method: Data for 199 071 patients with a first AMI during 2006–2017, including 3725 RA patients, and for anti-inflammatory medical treatment during the 6 months before a first AMI, were drawn from Swedish registries. Drugs were categorized as corticosteroids, non-steroidal anti-inflammatory drugs, conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs), tumour necrosis factor inhibitors (anti-TNFs), or other biological DMARDs. Multivariable logistic regression analysis was used to assess mortality associations up to 30 days and multivariable Cox proportional hazard models to assess associations from 31 to 365 days.

Results: No treatment was associated with survival within 30 days after the AMI. From 31 to 365 days post-AMI, corticosteroid treatment was associated with increased mortality [in RA: hazard ratio (HR) 1.43, 95% confidence interval (CI) 1.27–1.62; without RA: HR 1.37, 95% CI 1.33–1.41]. csDMARDs were associated with increased survival in RA patients (HR 0.86, 95% CI 0.78–0.96), as were anti-TNF treatments (HR 0.72, 95% CI 0.56–0.94). Among non-RA patients, csDMARDs were associated with increased mortality (HR 1.14, 95% CI 1.04–1.24).

Conclusion: Anti-inflammatory treatment was not associated with mortality within 30 days after a first AMI. From 31 to 365 days post-AMI, corticosteroid treatment was associated with increased mortality risk for all patients, and csDMARDs and anti-TNFs were associated with increased survival for RA patients.

OBJECTIVES: Female sex and anticitrullinated protein antibodies (ACPA) are associated with higher disease activity in rheumatoid arthritis (RA). Since disease-related inflammation is linked to cardiovascular risk, we explored whether sex and ACPA influenced the association between disease activity at study entry and cardiovascular risk in established RA. METHODS: We evaluated 4008 patients with prevalent RA from an international observational cohort enrolled between 1985 and 2012. Outcomes included major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction and stroke) and ischaemic cardiovascular events (iCVE: MACE, angina, revascularisation, transient ischaemic attack and peripheral arterial disease). Follow-up accrued from enrolment until the first event or censoring. Multivariable Cox models stratified by centre risk evaluated disease activity, sex, ACPA and their interactions. RESULTS: We documented 193 MACE and 299 iCVE. Disease activity and sex were associated with MACE (all p≤0.017) and iCVE (p≤0.005) but ACPA was only associated with MACE (p=0.043). A three-way interaction on MACE (p=0.034) but not iCVE was noted. Among ACPA-negative patients, disease activity was associated with MACE in males (HR 1.57 (95% CI 1.14 to 2.16)) but not females (p-for-interaction=0.022). Among ACPA-positive patients, neither the disease activity x sex interaction (p=0.929), nor main effect of disease activity on MACE (p=0.124) was significant, but male sex was (HR 1.61 (95% CI 1.15 to 2.27)). Among females, neither disease activity x ACPA interaction (p=0.523) nor disease activity (p=0.319) was significant for MACE, but ACPA was (HR 1.57 (95% CI 1.02 to 2.42)). CONCLUSIONS: The effect of disease activity at enrolment on cardiovascular risk in prevalent RA varies across patient groups with different sex and ACPA characteristics.

Objective: Pulmonary fibrosis (PF) is a severe extra-articular manifestation of rheumatoid arthritis (RA). This study aimed to externally validate a genetic risk score (GRS) and a combined risk score (CRS) for predicting the risk of RA-associated PF in an independent cohort of patients with early RA.

Methods: This study used an inception cohort of 1,118 patients diagnosed with RA from northern Sweden between 1996 and 2016. Clinical data were systematically collected, and genotyping was performed for 12 single-nucleotide polymorphisms (SNPs) associated with idiopathic PF. Statistical analyses, including logistic regression and area under the curve (AUC) assessments, were conducted to evaluate the performance of the GRS and in combination with clinical data as the CRS in predicting RA-PF development.

Results: Of the 1,115 patients with complete data, 60 (5.6%) were diagnosed with PF. PF was significantly associated with age, rheumatoid factor positivity, disease activity, and MUC5B (rs35705950) and FAM13A(rs2609255) SNPs. The GRS demonstrated a significant association with RA-PF (odds ratio 2.6, 95% confidence interval 1.6–4.5), whereas the CRS exhibited superior performance (AUC 0.75, P < 0.001) compared to the GRS alone (AUC 0.62). The combined risk score outperformed the GRS in discriminating RA-PF, indicating its potential utility in clinical practice.

Conclusion: This study provides external validation of the Veterans Affairs Rheumatoid Arthritis Registry interstitial lung disease GRS (VARA-ILD-GRS) and the VARA-ILD-CRS in an RA cohort, demonstrating their generalizability and effectiveness in identifying individuals at high risk for RA-ILD. The findings support the integration of genetic and clinical data in risk stratification models, which could significantly improve screening strategies for patients with RA at risk of developing PF. (Figure presented.).

Objective Autoantibodies are a key feature of rheumatoid arthritis (RA). They can be detected years before disease onset, but it is unknown if there is any pattern in the co-occurrence of antigen recognition or isotype profiles. A common signature could point to a unique initial trigger for autoantibody development. Therefore, we sought to determine if there is a pattern in antigen or isotype reactivity in pre-symptomatic cases and established RA.

Methods One pre-symptomatic cohort and one RA cohort were analysed for the co-occurrence of different isotypes of anti-modified protein antibodies (AMPA) and rheumatoid factor (RF). Patterns in autoantibody levels were investigated with clustering. Additionally, total IgG was measured in 1- year follow-up sera of a representative subgroup of the RA cohort.

Results While especially anti-citrullinated protein antibodies (ACPA) IgG and RF IgA co-occurred with other autoantibodies, no specific patterns emerged. In both cohorts, clusters of autoantibody levels were not determined by particular antigen reactivities or isotype. However, clusters were driven by elevated levels of several different AMPA, with distinct AMPA high- and low-level clusters. A broad IgG autoantibody profile was not accompanied by high total IgG levels.

Conclusion Autoantibody clusters are most likely not driven by AMPA specificity or isotype profile, neither before nor at RA onset, but are instead determined by a broad variety of autoantibodies. This indicates that the triggers for autoantibody development in RA do not skew the response towards certain autoreactivities or isotypes but rather lead to a broad and diverse autoantibody repertoire reflecting continuous and ongoing immune activation.

Objectives: To investigate the occurrence and dynamics of secretory component-containing antibodies towards citrullinated proteins (SC ACPA) in plasma from pre-symptomatic individuals subsequently developing rheumatoid arthritis (RA).

Methods: We studied 319 individuals who had donated plasma prior to RA onset (median predating time 4.7 years), whereof 181 also donated samples after diagnosis. One hundred individuals were randomly selected from the same biobank cohorts to serve as controls. SC ACPA, total secretory IgA (TSIgA) and IgG ACPA were analysed in plasma by enzyme-linked immunoassays.

Results: Circulating SC ACPA levels in pre-symptomatic individuals and RA patients were significantly increased compared with controls [median (interquartile range) 108 (108), 179 (248) and 12.5 (537) AU/ml, respectively; P < 0.001], and SC ACPA levels in RA patients were significantly increased compared with pre-symptomatic individuals (P < 0.001). SC ACPA increased, in terms of both levels and proportion of positive samples, closer to symptom onset and diagnosis. TSIgA was not elevated compared with controls either during the pre-dating time or after diagnosis. The earliest detected SC ACPA positive sample was 9 years before symptom onset, as compared with 11 years for IgG ACPA. Only two pre-dating samples were positive for SC ACPA and negative for IgG ACPA.

Conclusions: Circulating SC ACPA responses arise and magnify during the asymptomatic phase of disease development in a subgroup of RA patients. This suggests mucosal involvement prior to both symptom onset and subsequent arthritis. As mirrored in the circulation, however, SC ACPA does not seem to precede the IgG ACPA response.

Clonal hematopoiesis (CH) becomes more prevalent with aging and may influence inflammatory diseases by altering immune function. While CH of indeterminate potential (CHIP) promotes inflammation in nonmalignant conditions, its relationship with rheumatoid arthritis (RA) remains unknown. We analyzed CHIP mutations in RA using two population-level cohorts and patients with newly diagnosed RA. CHIP was associated with prevalent RA in 10,089 FINRISK study participants with whole-exome sequencing (OR, 2.06; P = 0.029) and in the FinnGen cohort (n = 520,210; OR, 1.49; P < 0.001) using single-nucleotide polymorphism array–based CHIP annotation. In FinnGen, CHIP was also associated with inferior overall survival in participants with RA (P = 0.013). In newly diagnosed RA (n = 573), DNMT3A-mutated seropositive patients had increased inflammatory markers and disease activity compared with patients without CHIP. In contrast, TET2 mutations were enriched in seronegative RA (P = 0.009). Our findings provide further evidence for the context-dependent association between CHIP and inflammation, with potential therapeutic implications.

Objective: Rheumatoid arthritis (RA) associated interstitial lung disease (ILD) is the most common pulmonary manifestations of RA, with a progressive course and a poor survival. An early detection and better treatment is essential to improve outcome. We evaluated 16 analytes that could be relevant for the development of RA ILD.

Method: In an inception cohort of 1118 early RA patients, pulmonary fibrosis (PF) were identified in 60 patients after a mean follow-up of 5.3 years using high resolution computer tomography (HRCT). As controls, 124 early RA patients without PF and 94 matched population controls without known rheumatic disease were studied. Analysis of antibodies against histones 3 and 4 derived citrullinated peptides (CitH3/H4), and cytokines/chemokines levels were performed in plasma samples collected at RA diagnosis using in-house ELISA and Luminex analysis.

Result: Anti-CitH3(114–135) antibodies were the only antibody with increased frequency and levels in patients with PF versus without PF. The highest OR for PF development were found when combining positivity for anti-CitH3(114–135) and -CitH4(31–50) antibodies, OR 2.26. Levels of IL1α, IL1ß, TNFα, VEGFA and MIPα remained significantly elevated in patients with PF compared without PF, after adjustments and Bonferroni corrections. Several of the cytokines/chemokines correlated significantly with the histone antibodies in patients without PF. Partial least squares discriminant analysis including antibodies against citrullinated histon peptides and cytokines/chemokines identified significantly in PF in non-smokers.

Conclusion: Antibodies against CitH3 peptides and several of the analysed cytokines/chemokines in samples collected at diagnosis were associated with subsequent delevopment of PF in patients with RA.

Objectives: To determine anticitrullinated protein antibody (ACPA) responses to novel peptides predicting the clinical outcomes of treatment-naïve early rheumatoid arthritis (RA) in the presymptomatic stage.

Methods: We analysed monoclonal ACPAs derived from RA patients, including a characterised protective ACPA (clone E4), along with plasma samples collected from 520 presymptomatic individuals, of whom 244 were also sampled at diagnosis of RA, and 530 population controls in Sweden. The validation cohort (The Nordic Rheumatic Diseases Strategy Trials and Registries, NORD-STAR) consisted of 690 treatment-naïve early RA patients. Responses to citrullinated or native alpha-enolase (ENO1) or peptidylarginine deiminase 4 (PAD4) peptides were analysed by bead-based multiplex flow immunoassay. Clinical outcomes included C-reactive protein (CRP) and the 28-joint disease activity score (DAS28) with its components: tender joint count (TJC), swollen joint count (SJC), and erythrocyte sedimentation rate (ESR).

Results: Monoclonal ACPAs displayed distinct binding patterns to ENO1 and PAD4 peptides. A time-dependent increase of ACPA response to citrullinated peptides was observed in the presymptomatic stage towards onset. In the presymptomatic (0.2-5 years before onset) and early RA stage, ACPA responses to several ENO1 and PAD4 peptides were associated with less severe RA, assessed as lower levels of CRP and DAS28 and its components. In early RA, the association was more pronounced in rheumatoid factor (RF)-negative patients based on lower SJC. In presymptomatic individuals, ACPA responses widely predicted lower disease activity in early RA and were more pronounced in 5 selected peptides.

Conclusions: Antibody responses to certain citrullinated epitopes are associated with lower disease activity in treatment-naïve early RA and appear years before symptom onset of RA.