Anti-citrullinated Protein Antibody Status Research Articles

Identification of circulating autoantibodies to non-modified proteins associated with ACPA status in early rheumatoid arthritis.

To discover autoantibodies to non-modified proteins associated with the presence/absence of anticitrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA). The autoantibody repertoire of 80 ACPA negative and 80 ACPA positive RA subjects from the Swedish population-based Epidemiological Investigation of RA (EIRA) cohort was screened using a suspension bead array built on protein fragments earlier described as autoimmunity targets. Four autoantibodies positive in the initial screening were validated in another set of EIRA samples containing 317 ACPA-positive, 302 ACPA-negative and 372 age- and sex-matched controls. The relationship between the four autoantibodies and lung abnormalities on high-resolution computed tomography (HRTC) was examined in 93 early RA patients from LURA cohort. Association between the autoantibodies, smoking and MHC class II alleles was assessed by logistic regression analysis. : Anti-ANOS1 and anti-MURC IgG levels were associated with ACPA-positive status (OR = 3.02; 95% CI 1.87-4.89; and OR = 1.86; 95% CI 1.16-2.97, respectively) and increased in ACPA-positive patients compared with controls. Anti-ANOS1 IgG was associated with smoking habit (OR = 2.11; 95% CI 1.22-3.69) and anti-MURC IgG with the presence of the MHC class II "shared-epitope" genes (OR = 1.95; 95% CI 1.11-3.46). Anti-TSPYL4 IgG was associated with ACPA-negative (OR = 0.41; 95% CI 0.19-0.89). Anti-TSPYL4 IgG and anti-MAP2K6 IgG levels were increased in the ACPA-negative patients compared with controls. Presence of anti-MAP2K6 IgG and anti-TSPYL4 IgG correlated negatively with HRCT-defined lung abnormalities. These four autoantibodies may be useful in diagnostics and in predicting clinical phenotypes of RA.

Country-level socioeconomic status relates geographical latitude to the onset of RA: a worldwide cross-sectional analysis in the METEOR registry

ObjectiveAge at rheumatoid arthritis (RA) onset varies by geographical latitude. We have investigated to what extent differences in patient-specific factors and country-level socioeconomic indicators explain this variability.MethodsPatients with RA from...

Patients with ACPA-positive and ACPA-negative rheumatoid arthritis show different serological autoantibody repertoires and autoantibody associations with disease activity

Patients with rheumatoid arthritis (RA) can test either positive or negative for circulating anti-citrullinated protein antibodies (ACPA) and are thereby categorized as ACPA-positive (ACPA+) or ACPA-negative (ACPA−), respectively. In this study, we aimed to elucidate a broader range of serological autoantibodies that could further explain immunological differences between patients with ACPA+ RA and ACPA− RA. On serum collected from adult patients with ACPA+ RA (n = 32), ACPA− RA (n = 30), and matched healthy controls (n = 30), we used a highly multiplex autoantibody profiling assay to screen for over 1600 IgG autoantibodies that target full-length, correctly folded, native human proteins. We identified differences in serum autoantibodies between patients with ACPA+ RA and ACPA− RA compared with healthy controls. Specifically, we found 22 and 19 autoantibodies with significantly higher abundances in ACPA+ RA patients and ACPA− RA patients, respectively. Among these two sets of autoantibodies, only one autoantibody (anti-GTF2A2) was common in both comparisons; this provides further evidence of immunological differences between these two RA subgroups despite sharing similar symptoms. On the other hand, we identified 30 and 25 autoantibodies with lower abundances in ACPA+ RA and ACPA− RA, respectively, of which 8 autoantibodies were common in both comparisons; we report for the first time that the depletion of certain autoantibodies may be linked to this autoimmune disease. Functional enrichment analysis of the protein antigens targeted by these autoantibodies showed an over-representation of a range of essential biological processes, including programmed cell death, metabolism, and signal transduction. Lastly, we found that autoantibodies correlate with Clinical Disease Activity Index, but associate differently depending on patients’ ACPA status. In all, we present candidate autoantibody biomarker signatures associated with ACPA status and disease activity in RA, providing a promising avenue for patient stratification and diagnostics.

Association of the serological status of rheumatoid arthritis patients with two circulating protein biomarkers: A useful tool for precision medicine strategies.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints and presence of systemic autoantibodies, with a great clinical and molecular heterogeneity. Rheumatoid Factor (RF) and anti-citrullinated protein antibodies (ACPA) are routinely used for the diagnosis of RA. However, additional serological markers are needed to improve the clinical management of this disease, allowing for better patient stratification and the desirable application of precision medicine strategies. In the present study, we investigated those systemic molecular changes that are associated with the RF and ACPA status of RA patients. To achieve this objective, we followed a proteomic biomarker pipeline from the discovery phase to validation. First, we performed an iTRAQ-based quantitative proteomic experiment on serum samples from the RA cohort of the Hospital of Santiago de Compostela (CHUS). In this discovery phase, serum samples from the CHUS cohort were pooled according to their RF/ACPA status. Shotgun analysis revealed that, in comparison with the double negative group (RF-/ACPA-), the abundance of 12 proteins was altered in the RF+/ACPA+ pool, 16 in the RF+/ACPA- pool and 10 in the RF-/ACPA+ pool. Vitamin D binding protein and haptoglobin were the unique proteins increased in all the comparisons. For the verification phase, 80 samples from the same cohort were analyzed individually. To this end, we developed a Multiple Reaction Monitoring (MRM) method that was employed in a comprehensive targeted analysis with the aim of verifying the results obtained in the discovery phase. Thirty-one peptides belonging to 12 proteins associated with RF and/or ACPA status were quantified by MRM. In a final validation phase, the serum levels of alpha-1-acid glycoprotein 1 (A1AG1), haptoglobin (HPT) and retinol-binding protein 4 (RET4) were measured by immunoassays in the RA cohort of the Hospital of A Coruña (HUAC). The increase of two of these putative biomarkers in the double seropositive group was validated in 260 patients from this cohort (p = 0.009 A1AG1; p = 0.003 HPT). The increased level of A1AG1 showed association with RF rather than ACPA (p = 0.023), whereas HPT showed association with ACPA rather than RF (p = 0.013). Altogether, this study has allowed a further classification of the RA seropositive patients into two novel clusters: RF+A1AG+ and ACPA+HPT+. The determination of A1AG1 and HPT in serum would provide novel information useful for RA patient stratification, which could facilitate the effective implementation of personalized medicine in routine clinical practice.

Patients with seronegative rheumatoid arthritis have a different phenotype than seropositive patients: A clinical and ultrasound study.

IntroductionRheumatoid arthritis (RA) is an inflammatory disease whose clinical phenotype largely depends on the presence of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). Seronegative RA appears to be a less severe disease, but this remains controversial. This study aimed to assess whether seronegative patients show a less severe disease than seropositive patients.MethodsA cross-sectional study was conducted on RA outpatients from a single center. Clinical activity scales, laboratory evaluations, and cardiovascular risk scores were assessed. Musculoskeletal ultrasound (US) examinations were performed.ResultsOne hundred and fourteen patients were enrolled. Eighty-five were seropositive (76% women) and 29 seronegative (93% women). Seropositive patients had a younger age at disease onset (43 ± 14 vs. 54 ± 11; p = 0.001) and used sulfasalazine (47 vs. 17%; p = 0.004) and glucocorticoids (36 vs. 10%; p = 0.007) more frequently. No differences in clinical activity scales and in 10-year cardiovascular risk were observed. Pathological US data were found more frequently in seropositive patients in the 2nd metacarpophalangeal (MCP) joint, both in grayscale (71 vs. 38%; p = 0.008) and in power Doppler (PD; 53 vs. 9%; p < 0.001); erosions (36 vs. 9%; p = 0.020) were also more frequent. We found greater severity of PD signals in the 2nd MCP and 3rd MCP joints of the seropositive patients, while synovitis severity was higher only in the 2nd MCP joints. The percentage of total joints with erosions (9 vs. 1%; p < 0.001) and 2nd MCP joints with erosions (25 vs. 7%; p < 0.001) was higher in seropositive patients.ConclusionRA patients show a differentiated phenotype according to their ACPA and RF status. In seronegative patients, RA begins later in life and has a lower requirement for antirheumatic therapies. On US evaluation, seropositive patients show more joint damage, especially in MCP joints. Despite this, long-term cardiovascular risk is similar among RA patients, regardless of their RF and ACPA status.

The Role of Shared Epitope in Rheumatoid Arthritis Prognosis in Relation to Anti-Citrullinated Protein Antibody Positivity.

IntroductionShared epitope (SE) is present in high proportions of anti-citrullinated protein antibody (ACPA) + patients with rheumatoid arthritis (RA) and is associated with poor prognosis. We assessed the role of SE in RA prognosis, in relation to ACPA positivity.MethodsPatients enrolled in the Brigham and Women’s RA Sequential Study were included. Changes from baseline in disease activity (Disease Activity Score in 28 joints using C-reactive protein [DAS28 (CRP)], Clinical Disease Activity Index [CDAI], Simplified Disease Activity Index [SDAI]) to 1 year were assessed. Baseline characteristics were compared by SE and ACPA status (±; chi-squared, Kruskal-Wallis). Association between number of SE alleles and ACPA status (logistic regression models), relationships between baseline characteristics and changes in disease activity (adjusted linear regression model), and effect of ACPA on the association between SE and changes in disease activity (mediation analysis) were studied.ResultsNine hundred twenty-six patients were included. SE + versus SE − patients had significantly longer disease duration and higher disease activity scores and were more likely to have erosive disease, have higher comorbidity burden, and be RF + (all p < 0.05). Among patients with one or two SE alleles (vs. 0), odds of being ACPA + were 1.97 (p = 0.0003) and 3.82 (p < 0.0001), respectively. SE + versus SE − patients had worse disease activity scores as indicated by mean increases in DAS28 (CRP) of 0.22, CDAI of 2.07, and SDAI of 2.43 over 1 year (all p < 0.05). Direct effect of SE + accounted for 76.4–80.1% of total effect in disease activity increases.ConclusionsSE is strongly associated with ACPA positivity and higher disease activity in patients with RA. SE was associated with greater increases in disease activity over 1 year, which was partially mediated by the presence of ACPA.Trial RegistrationClinicalTrials.gov identifier: NCT01793103; registration date: February 15, 2013, retrospectively registered.

Unraveling heterogeneity within ACPA-negative rheumatoid arthritis: the subgroup of patients with a strong clinical and serological response to initiation of DMARD treatment favor disease resolution

BackgroundRheumatoid arthritis (RA) is a heterogeneous disease, as evidenced by the differences in long-term outcomes. This applies especially to anti-citrullinated protein antibodies (ACPA)-negative RA, where a proportion achieves sustained DMARD-free remission (SDFR; sustained absence of synovitis after DMARD cessation). Differentiation of RA patients who will achieve SDFR can guide personalized treatment/tapering strategies. Although this subgroup remains scarcely discerned, previous research demonstrated that these RA patients are characterized by an early clinical response (DAS remission after 4 months) after DMARD start. We studied whether, in addition to this clinical response, a specific biomarker response can further distinguish the subgroup of RA patients most likely to achieve SDFR.MethodsIn 266 RA patients, levels of 12 biomarkers (SAA/CRP/MMP-1/MMP-3/resistin/leptin/IL-6/TNF-R1/YKL-40/EGF/VEGF/VCAM-1), in the first 2 years after diagnosis, were studied in relation to SDFR, stratified for ACPA status. Subsequently, biomarkers associated with SDFR development were combined with early DAS remission to study its additional value in defining subgroups. Since most biomarker levels are not routinely measured in clinical practice, we explored how this subgroup can be clinically recognized.ResultsACPA-negative RA patients achieving SDFR were characterized by high baseline levels and stronger decline in MMP-1/MMP-3/SAA/CRP after DMARD-start, respectively 1.30×/1.44×/2.12×/2.24× stronger. This effect was absent in ACPA-positive RA. In ACPA-negative RA, a strong biomarker decline is associated with early DAS remission. The combination of both declines (clinical, biomarker) was present in a subgroup of ACPA-negative RA patients achieving SDFR. This subgroup can be clinically recognized by the combination of high baseline CRP levels (≥ 3 times ULN), and early DAS remission (DAS4 months < 1.6). This latter was replicated in independent ACPA-negative RA patients.ConclusionsACPA-negative RA patients with early DAS remission and a strong biomarker response (or baseline CRP levels ≥ 3× ULN) are most likely to achieve SDFR later on. This could guide personalized decisions on DMARD tapering/cessation in ACPA-negative RA.

Baseline Anti-Citrullinated Protein Antibody Status and Response to Abatacept or Non-TNFi Biologic/Targeted-Synthetic DMARDs: US Observational Study of Patients with RA.

IntroductionPatients with rheumatoid arthritis (RA) may respond to treatments differently based on their underlying serology and biomarker status, but real-world data comparing treatment responses to abatacept versus other non-TNFi biologic or targeted-synthetic DMARDs by anti-citrullinated protein antibody (ACPA) status remain limited. We assessed the association between ACPA status and response to treatment in patients with RA.MethodsAdults from CorEvitas’ RA Registry were identified who initiated abatacept, rituximab, tocilizumab, or tofacitinib, and had ACPA measured at/prior to treatment initiation and at the 6-month follow-up visit. Three cohorts were included: abatacept/rituximab (2006–2019), abatacept/tocilizumab (2010–2019), and abatacept/tofacitinib (2012–2019). Patient characteristics at initiation were compared by ACPA status (positive [+], anti-cyclic citrullinated peptide-2 [anti-CCP2] ≥ 20 U/ml; negative [−], anti-CCP2 < 20 U/ml). Outcomes over 6 months: changes in Clinical Disease Activity Index (CDAI), modified Health Assessment Questionnaire (mHAQ), patient global assessment (PGA) scores, and proportion of patients achieving a clinical response. Adjusted mean differences and odds ratios were estimated using mixed-effects linear regression models.ResultsOverall, 982 abatacept, 246 rituximab, 404 tocilizumab, and 429 tofacitinib initiators were identified. ACPA+ (vs. ACPA−) patients had longer disease duration and more erosive disease. During most time periods adjusted mean changes in CDAI, mHAQ, and PGA scores and the proportion of patients achieving a clinical response were significantly higher for ACPA+ versus ACPA− patients initiating abatacept. Adjusted mean change in PGA score and patient fatigue were significantly higher for ACPA+ versus ACPA− patients initiating rituximab. No significant differences were seen by ACPA status for patients initiating tocilizumab or tofacitinib.ConclusionsPatients who initiated abatacept or rituximab and were ACPA+ had a greater clinical response at 6-month follow-up post index compared to patients who were ACPA– treated with the same biologic.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-021-00401-0.

Immunoprofiling of early, untreated rheumatoid arthritis using mass cytometry reveals an activated basophil subset inversely linked to ACPA status

BackgroundAutoantibody production is a hallmark of rheumatoid arthritis (RA). Anti-citrullinated protein antibodies (ACPA) are highly disease-specific, and their presence is associated with more severe disease and poor prognosis compared to ACPA-negative patients. However, the immune cell composition associated with antibody-positive/negative disease is incompletely defined. Mass cytometry (MC) is a high-dimensional technique offering new possibilities in the determination of the immune cell composition in rheumatic diseases. Here, we set up a broad phenotyping panel to study the immune cell profile of early untreated RA to investigate if specific immune cell subsets are associated with ACPA+ versus ACPA− RA.MethodsFreshly obtained PBMCs of early, untreated RA patients (8 ACPA+ and 7 ACPA−) were analysed using a 36-marker MC panel, including markers related to various immune lineages. Data were processed using Cytosplore for dimensional reduction (HSNE) and clustering. Groups were compared using Cytofast. A second validation cohort of cryopreserved PBMCs obtained from early RA patients (27 ACPA+ and 20 ACPA−) was used to confirm MC data by flow cytometry (FC). FC data were processed and analysed using both an unsupervised analysis pipeline and through manual gating.ResultsMC indicated no differences when comparing major immune lineages (i.e. monocytes, T and B cells), but highlighted two innate subsets: CD62L+ basophils (p = 0.33) and a subset of CD16− NK cells (p = 0.063). Although the NK cell subset did not replicate by FC, FC replication confirmed the difference in CD62L+ basophil frequency when comparing ACPA+ to ACPA− patients (mean 0.32% vs. 0.13%; p = 0.01).ConclusionsAlthough no differences in major lineages were found between early ACPA+ and ACPA− RA, this study identified the reduced presence of activated basophils in ACPA-negative disease as compared to ACPA-positive disease and thereby provides the first evidence for a connection between activated basophils and ACPA status.

Influence of selected demographic and clinical factors on the treatment of rheumatoid arthritis – a long-term follow-up

Robert Kruszewski, Bartłomiej Kisiel, Witold TłustochowiczMethotrexate is recommended as a first-line drug in the treatment of rheumatoid arthritis, however, clinical practice often requires a change in the therapeutic approach. Our objective was to evaluate the influence of several demographic and diseaserelated factors on the treatment of rheumatoid arthritis. A group of 143 rheumatoid arthritis patients, initially treated with methotrexate in monotherapy or in combination with glucocorticoids, was followed for an average of 7.5 years. A search for associations between age, sex, disease onset age, disease duration, body mass index, smoking, rheumatoid factor and anticitrullinated protein antibodies status, initial disease activity, bone erosions and rheumatoid arthritis treatment during the follow-up was performed. Patients receiving biological therapy were younger than those on other types of treatment (50.57 ± 13.39 vs. 58.86 ± 11.67 years; p = 0.0013), had slightly lower disease onset age (41.78±13.03 vs. 47.88 ± 13.74 years; p = 0.035) and more prevalent high levels of anti-citrullinated protein antibodies (91% vs. 66%; p = 0.02). On the other hand, patients on methotrexate monotherapy were older than those receiving other therapies (61.51 ± 10.86 vs. 53.97±12.61 years; p = 0.0002) and had slightly higher disease onset age (52.08 ± 13.20 vs. 42.55 ± 12.82 years; p = 0.000026). Higher initial disease activity (DAS28) was associated with a need for prolonged treatment with biological agents or biological therapy with addition of synthetic disease modifying antirheumatic drugs other than methotrexate. We found no relationships between sex, disease duration, body mass index, smoking or radiological erosions and the type of received disease modifying antirheumatic drug. Patient’s actual age and disease onset age seem to have the most significant impact on rheumatoid arthritis treatment course.

AB0150 ACPA-STATUS AND RHEUMATOID ARTHRITIS: MUCH MORE TO BE REVEALED!

Background:Anti-citrullinated protein antibodies (ACPA) are commonly associated with Rheumatoid arthritis (RA). RA is, therefore, classified as immunopositive or immunonegative, with disparate mechanisms in predisposition.Objectives:Our study aimed to determine the baseline characteristics and differences of ACPA-positive and ACPA-negative RA.Methods:We conducted a cross-sectional study including 224 patients with RA. All patients fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism RA classification criteria. The patients were divided according to their ACPA status into two groups: ACPA-positive group (G1) and ACPA-negative group (G2). We compared clinical, radiological, and laboratory findings between the two groups, as well as extra-articular manifestations, comorbidities including fractures and osteoporosis. The Fracture Risk Assessment Tool (FRAX) was used to estimate the 10-year probability of major osteoporotic fracture (MOF) and also hip fracture (FH).Results:Of the 224 patients, 31.6% were negative for ACPA (n=71). Female predominance was found in both groups with a sex ratio of 0.25 (p=0.203). ACPA-negative subjects were younger (57±11 versus 59±12 years) (p= 0.305).The initial presentation of RA was different between the two groups without reaching statistical significance. In the ACPA-negative group, alteration of general condition was more frequent (16.9% in G2 versus 13.7% in G1) (p=0.533), with a tendency to oligo-articular onset (18.5% in G2 versus 6.7% in G1) (p=0.737). ACPA-positivity was more associated with an acute start of symptoms (10.4% in G1 versus 8.4% in G2) (p=0.639)There was no significant difference in the mean DAS28-VS (5.2±1.1 in G2 versus 5.5±1.3 in G1) and DAS28-CRP levels (5±1 in G2 versus 5.3±1.2 in G1) (p=0.069 and p=0.098 respectively).ACPA-positive RA was, however, significantly associated with more structural joint damage: erosions (55.9±53 in G1 versus 78±36 in G2, p=0.01), joint space narrowing (50.4±45.5 in G1 versus 33.1±36.6 in G2, p=0.003), Sharp/van der Heijde radiographic score (126.6 ±103.2 in G1 versus 88.8±81.5 in G2, p=0.004). ACPA-positive RA patients had more atlantoaxial dislocation: 20.2% in G1 versus 7% in G2 (p=0.012). There was no significant difference in hip involvement (9.8% in G1 versus 14% G2) (p=0.344).There were no significant differences in extra-articular manifestations between the two groups: Rheumatoid nodules (10.4% in G1 versus 18.3% in G2) (p=0.891), Sjögren’s syndrome (16.3% in G1 versus 16.9% in G2)(p=0.715), amyloidosis (0.6% in G1) (p=1), pulmonary fibrosis (5.8% in G1 versus 4.2% in G2) (p=0.757), neurological signs (4.5% in in G1 versus 5.6% in G2) (p=0.733), anaemia (5.8% in G1 versus 1.4% in G2) (p=0.175).When analyzing comorbidities, no significant differences were found: diabetes (10.4% in G1 versus 18.3% in G2) (p=0.103), cardiovascular diseases (19.6% in G1) (p=1), neurological diseases (0.06% in G1 versus 1.4% in G2) (p=0.534), dysthyroidism (2.6% in G1 versus 5.6% in G2) (p=0.267), dyslipidemia (3.2% in G1 versus 4.2% in G2) (p=0.711), cancer (1.3% in G1) (p=1). There were neither significant differences in the prevalence of fracture (21.5% in G1 versus 18.3% in G2) (p=0.574), and osteoporosis (23.6% in G1 versus 29.5% in G2) (p=0.347), between the two groups. However, ACPA-positive patients presented with a significantly higher FRAX score of MOF (2±2.8 in G1 versus 1.2±1 in G2) (p=0.006), and FRAX score of FH (0,9±1.8 in G1 versus 0.3±0.5 in G2) (p=0.003).Conclusion:ACPA status appears to influence both the clinical presentation and radiological progression of RA patients. ACPA-positive patients present with an acute start of symptoms, with more structural damages and atlantoaxial dislocation. Comorbidities, including osteoporosis, does not seem affected by ACPA status. However, regardless of osteoporosis, ACPA-positivity is associated with a higher probability of major osteoporotic and hip fractures. Further research is needed to clarify this relationship.Disclosure of Interests:None declared

Elevated Anti-Citrullinated Protein Antibodies Prior to Rheumatoid Arthritis Diagnosis and Risks for Chronic Obstructive Pulmonary Disease or Asthma.

To investigate elevation of anti-citrullinated protein antibodies (ACPAs) before diagnosis of rheumatoid arthritis (RA) and risks for chronic obstructive pulmonary disease (COPD) or asthma. We performed a matched cohort study nested within the Nurses' Health Studies among women who donated blood. Women with incident RA after blood draw (self-reported, then confirmed by medical records) were each matched to 3 controls by age, cohort, year, and menopausal factors. Pre-RA ACPA positivity was defined as >99th percentile of control distribution by a research assay or by cyclic citrullinated peptide in a subset. Incident COPD and asthma after index date (date of blood draw) were identified by questionnaires. Cox regression estimated hazard ratios (HRs) for incident COPD or asthma (in separate analyses) associated with pre-RA, pre-RA ACPA+, or pre-RA ACPA- phenotypes each compared to their matched non-RA controls. We analyzed 283 women who were pre-RA and 842 controls; blood was donated a mean ± SD of 9.7 ± 5.8 years before RA diagnosis. Fifty-nine women (20.8%) were pre-RA ACPA+. There were 107 cases of incident COPD and 105 incident asthma cases during 21,489 person-years of follow-up. Pre-RA ACPA+ was associated with increased COPD risk (HR 3.04 [95% confidence interval (95% CI) 1.33-7.00]) after adjusting for covariates including smoking pack-years. Pre-RA ACPA+ had an HR for asthma of 1.74 (multivariable 95% CI 0.72-4.24), similar to the risk of asthma for pre-RA ACPA- (HR 1.65 [95% CI 1.11-2.46]). Women with elevated ACPA before RA diagnosis had increased risk for developing COPD compared to controls. Women who later developed RA were more likely to develop asthma than controls, regardless of pre-RA ACPA status.

Respiratory Diseases as Risk Factors for Seropositive and Seronegative Rheumatoid Arthritis and in Relation to Smoking.

The link and interplay between different airway exposures and rheumatoid arthritis (RA) risk are unclear. This study was undertaken to determine whether respiratory disease is associated with development of RA, and specifically to examine this relationship by RA serostatus and smoking exposure. Using data from the Epidemiological Investigation of Rheumatoid Arthritis study, this analysis included 1,631 incident RA cases and 3,283 matched controls recruited from 2006 to 2016. Linking these individuals to the National Patient Register provided information on past acute or chronic, upper or lower respiratory disease diagnoses. For each disease group, we estimated adjusted odds ratios (ORadj ) with 95% confidence intervals (95% CI) for RA, using logistic regression models adjusted for age, sex, residential area, body mass index, and education both overall and stratified by anti-citrullinated protein antibody (ACPA)/rheumatoid factor (RF) status and by smoking status. Respiratory disease diagnoses were associated with risk of RA, with an ORadj of 1.2 for acute upper respiratory disease (95% CI 0.8-1.7), 1.4 for chronic upper respiratory disease (95% CI 1.1-1.9), 2.4 for acute lower respiratory disease (95% CI 1.5-3.6), and 1.6 for chronic lower respiratory disease (95% CI 1.5-3.6). These associations were present irrespective of RF or ACPA status, though the association was somewhat stronger for ACPA/RF-positive than ACPA/RF-negative RA. The association between any respiratory disease and RA was stronger for nonsmokers (ORadj 2.1 [95% CI 1.5-2.9]) than for smokers (ORadj 1.2 [95% CI 0.9-1.5]). Respiratory diseases increase the risk for both seropositive and seronegative RA, but only among nonsmokers. These findings raise the hypothesis that smoking and airway disease are associated with RA development through partly different mechanisms.

Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial

ObjectiveTo evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis.DesignInvestigator initiated, randomised, open label,...

Association of a Serum Protein Signature With Rheumatoid Arthritis Development.

The pathophysiologic events that precede the onset of rheumatoid arthritis (RA) remain incompletely understood. This study was undertaken to identify changes in the serum proteome that precede the onset of RA, with the aim of providing new insights into the pathogenic mechanisms that lead to its development. In a cohort of first-degree relatives of Indigenous North American RA patients, the SomaScan proteomics platform was used to determine the levels of 1,307 proteins in multiple longitudinal serum samples from 17 individuals who were followed up prospectively to the time of disease onset. Proteomic signatures from this group of individuals (designated the progressor group) were compared to those in a group of individuals who were considered at risk of developing RA, stratified as either positive (n = 63) or negative (n = 47) for anti-citrullinated protein antibodies (ACPAs) (designated the at-risk group). Machine learning was used to identify a protein signature that could accurately classify those individuals at highest risk of future RA development. A preclinical proteomic signature that differentiated RA progressors from at-risk individuals, irrespective of ACPA status, was identified (area under the curve 0.913, accuracy 91.2%). Importantly, the predictive preclinical proteomic signature was present not only in serum samples obtained close to the onset of RA, but also in serum samples obtained a median of 30.9 months prior to onset. Network analysis implicated the activation of Toll-like receptor 2 and production of tumor necrosis factor and interleukin-1 as key events that precede RA progression. Alterations in the serum proteome in the preclinical phase of RA can emerge years prior to the onset of disease. Our findings suggest that the serum proteome provides a rich source of proteins serving both to classify at-risk individuals and to identify molecular pathways involved in the development of clinically detectable RA.

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.

Cardiovascular risk in persons at risk of developing rheumatoid arthritis.

BackgroundRheumatoid arthritis (RA) is associated with an increased cardiovascular disease (CVD) risk which may start even before diagnosis. To explore this CVD risk prior to RA, we determined multiple risk factors and two 10-year clinical risk scores in a cohort of individuals at-risk of RA. We also analyzed associations with arthritis development and autoantibody status and compared a subset of at-risk individuals to an age and sex matched seronegative control group.MethodsIn a cohort of 555 consecutive arthralgia patients positive for rheumatoid factor (RF) and / or anti-citrullinated protein antibody (ACPA) we retrospectively identified patients with preclinical arthritis (i.e. those who developed arthritis), and non-arthritis patients (those without arthritis development during maximum 5 years follow up). Demographics, CVD risk factors and the 10-year cardiovascular risk according to the SCORE and QRISK3 system were determined at baseline.ResultsPreclinical arthritis patients (n = 188) had a higher heart rate (68 vs 63 bpm, p = 0.048) and lower cholesterol (5.2 mmol/l vs 5.5, p = 0.006), HDL (1.0 mmol/l vs 1.1, p0.003) and ApoB (0.85 g/l vs 0.91, p = 0.011) compared to non-arthritis patients (n = 367). Lipid levels were associated with ACPA status in both the preclinical arthritis and non-arthritis group. Ten-year CVD risk scores did not differ between preclinical arthritis and non-arthritis patients, in total, 7% (SCORE) and 8% (QRISK3) of seropositive arthralgia patients were classified as high risk. Seropositive at-risk patients (n = 71) had higher total cholesterol (5.4 vs 4.9, p<0.001), TC/HDL ratio (4.0 vs 3.0, p<0.001), triglycerides (1.4 vs 1.0, p = 0.001), ApoB (1.0 vs 0.9, p = 0.019) and 10-year risk scores (median SCORE 1.0 vs 0.0, p = 0.030 and median QRISK3 4.4 vs 3.1, p<0.001) compared to seronegative controls.ConclusionOur results suggest that lipid changes commence prior to RA diagnosis and that ACPAs might play a role.

Presence of anti-citrullinated protein antibodies and costs and disease activity in early rheumatoid arthritis - a 3-year follow-up

Objective: To analyse healthcare utilization, loss of productivity, and disease activity in relation to presence of anti-citrullinated protein antibodies (ACPAs). Method: In total, 447 ACPA-positive and 224 ACPA-negative patients from two early rheumatoid arthritis cohorts, recruited 1996–1998 (cohort 1) and 2006–2009 (cohort 2), were followed during 3 years. Data on disease activity were collected, and patients reported healthcare utilization and days lost from work. Disease activity, healthcare costs, and loss of productivity were compared between ACPA groups. Linear regression was performed, controlling for confounders. Results: Healthcare costs did not differ significantly by ACPA status (EUR 3214 for vs EUR 2174 for ACPA-positive vs ACPA-negative patients in cohort 1, ns; EUR 4150 vs EUR 3820 in cohort 2, ns). Corresponding values for loss of productivity were EUR 9148 vs EUR 7916 (ns) and EUR 5857 vs EUR 5995 (ns). Total prescription of traditional disease-modifying anti-rheumatic drugs was higher in cohort 2 than in cohort 1. Methotrexate prescription was higher in ACPA-positive patients, but biologics did not differ significantly between ACPA groups. Disease activity was significantly more improved in cohort 2, but there was no difference in achieving remission in relation to ACPA status. In cohort 1, 25% of ACPA-positive patients were in remission vs 31% of ACPA-negative (ns) and in cohort 2, 55% vs 60% (ns). Conclusions: With increasing drug treatment for both ACPA-positive and ACPA-negative patients, outcome in ACPA-positive was no more severe than in ACPA-negative patients. Healthcare costs and loss of productivity were similar in the two groups.

AB0295 CHANGE IN DISEASE ACTIVITY AND TREATMENT RESPONSE AFTER ABATACEPT TREATMENT FOR RHEUMATOID ARTHRITIS: REAL-WORLD EVIDENCE FROM THE UK

Background:Patients with moderate to severe active rheumatoid arthritis (RA) may be treated with biological disease-modifying antirheumatic drugs (bDMARDs), such as abatacept, after treatment failure with conventional synthetic DMARDs (csDMARDs). Abatacept has shown equivalent efficiency with other targeted therapies for RA in clinical trials and network meta-analyses. However, there is limited real-world evidence on patient outcomes associated with abatacept treatment in UK routine clinical practice.Objectives:To describe the clinical outcomes of RA patients treated with abatacept in UK real-world clinical practice.Methods:A multi-centre, retrospective observational study was undertaken in RA patients treated with abatacept at any line of therapy (LOT). Data were extracted from medical records at four UK hospitals. Patients aged 18 years or older who received abatacept between 1 January 2013 and 31 December 2017 were included. The index date was the date of first bDMARD initiation, with follow-up from index date to latest RA clinic visit, death or 31 December 2017, whichever occurred first.Clinical outcomes (disease activity and response to treatment) were measured using the 28-joint Disease Activity Score based on erythrocyte sedimentation rate (DAS28-ESR) and European League Against Rheumatism (EULAR) response criteria1-3.Results:The study included 213 patients (mean age 55.2 years, 71.4% female, 7.0 years mean duration of RA at index date). Where ACPA and RF status were recorded, 66.1% of patients were anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF) positive at index. Mean DAS28-ESR at index was 6.2 (SD 1.0) and 80.9% of patients were categorised with high disease activity.Irrespective of LOT, changes in DAS28-ESR (where recorded) from LOT initiation among patients treated with abatacept versus other bDMARDs were -1.59 vs -1.56 (LS mean (SE): -0.04; 95% CI: -0.45,0.38; p=0.86) at 6 months and -1.98 vs -1.42 (LS mean (SE): -0.56; 95% CI: -1.04,-0.07; p=0.03) at 12 months, respectively. Table 1 shows that compared with other bDMARDs, patients treated with abatacept at any LOT experienced good response to treatment at 6 months (22.8%, n= 21/92 vs 15.9%, n= 24/151) and 12 months (27.9%, n= 17/61 vs 20.5%, n= 24/117) according to EULAR criteria.Table1.Treatment response at 6 and 12 months after initiation of any LOT*EULAR response6 months12 monthsAbatacept,n = 92Other bDMARDs,n = 151Abatacept,n = 61Other bDMARDs,n = 117Good21 (22.8%)24 (15.9%)17 (27.9%)24 (20.5%)Moderate38 (41.3%)60 (39.7%)22 (36.1%)40 (34.2%)None33 (35.9%)67 (44.4%)22 (36.1%)53 (45.3%)n = number of unique LOTs in which a patient has both a DAS28-ESR collected at initiation and 6 and/or 12 months (a patient may be included in this analysis multiple times)Patients who received abatacept remained on treatment for significantly longer than patients who received other bDMARDs at LOT1 (median 53.4 vs 17.4 months; p&lt;0.01) (Figure 1) and at LOT2 (median 40.1 vs 17.1 months; p&lt;0.01).Figure 1.Time on treatment from first LOT initiation, abatacept versus other bDMARDsConclusion:RA patients who received bDMARDs, including abatacept, experienced reduced disease activity. These findings are comparable with those from a European, multicentre, observational study on patients receiving abatacept4. The mechanisms associated with such clinical benefit should be elucidated in future research.

A budget impact analysis for making treatment decisions based on anti-cyclic citrullinated peptide (anti-CCP) testing in rheumatoid arthritis

Aim: Given that rheumatoid arthritis (RA) patients with high anti-citrullinated protein antibodies (ACPA) titer values respond well to abatacept, the aim of this study was to estimate the annual budget impact of anti-cyclic citrullinated peptide (anti-CCP) testing and treatment selection based on anti-CCP test results.Materials and methods: Budget impact analysis was conducted for patients with moderate-to-severe RA on biologic or Janus kinase inhibitor (JAKi) treatment from a hypothetical US commercial payer perspective. The following market scenarios were compared: (1) 90% of target patients receive anti-CCP testing and the results of anti-CCP testing do not impact the treatment selection; (2) 100% of target patients receive anti-CCP testing and the results of anti-CCP testing have an impact on treatment selection such that an increased proportion of patients with high titer of ACPA receive abatacept. A hypothetical assumption was made that the use of abatacept would be increased by 2% in Scenario 2 versus 1. Scenario analyses were conducted by varying the target population and rebate rates.Results: In a hypothetical health plan with one million insured adults, 2,181 patients would be on a biologic or JAKi treatment for moderate-to-severe RA. In Scenario 1, the anti-CCP test cost was $186,155 and annual treatment cost was $101,854,295, totaling to $102,040,450. In Scenario 2, the anti-CCP test cost increased by $20,684 and treatment cost increased by $160,467, totaling an overall budget increase of $181,151. This was equivalent to a per member per month (PMPM) increase of $0.015. The budget impact results were consistently negligible across the scenario analyses.Limitations: The analysis only considered testing and medication costs. Some parameters used in the analysis, such as the rebate rates, are not generalizable and health plan-specific.Conclusions: Testing RA patients to learn their ACPA status and increasing use of abatacept among high-titer ACPA patients result in a small increase in the total budget (<2 cents PMPM).