Autoantibody-negative Rheumatoid Arthritis Research Articles

Early identification of rheumatoid arthritis: does it induce treatment-related cost savings?

ObjectiveEarly diagnosis and treatment-start is key for rheumatoid arthritis (RA), but the economic effect of an early versus a later diagnosis has never been investigated. We aimed to investigate whether...

The Genetic, Environmental, and Immunopathological Complexity of Autoantibody-Negative Rheumatoid Arthritis.

Differences in clinical presentation, response to treatment, and long-term outcomes between autoantibody-positive and -negative rheumatoid arthritis (RA) highlight the need for a better comprehension of the immunopathogenic events underlying the two disease subtypes. Whilst the drivers and perpetuators of autoimmunity in autoantibody-positive RA have started to be disclosed, autoantibody-negative RA remains puzzling, also due its wide phenotypic heterogeneity and its possible misdiagnosis. Genetic susceptibility appears to mostly rely on class I HLA genes and a number of yet unidentified non-HLA loci. On the background of such variable genetic predisposition, multiple exogeneous, endogenous, and stochastic factors, some of which are not shared with autoantibody-positive RA, contribute to the onset of the inflammatory cascade. In a proportion of the patients, the immunopathology of synovitis, at least in the initial stages, appears largely myeloid driven, with abundant production of proinflammatory cytokines and only minor involvement of cells of the adaptive immune system. Better understanding of the complexity of autoantibody-negative RA is still needed in order to open new avenues for targeted intervention and improve clinical outcomes.

POS1258 MISSING THE WINDOW OF OPPORTUNITY: EARLY ARTHRITIS CLINICS IN TIMES OF COVID-19

Background:The outcomes of patients with chronic inflammatory arthritis (IA), such as rheumatoid arthritis (RA), have dramatically improved over the past 20 years. Earlier identification of IA and prompter treatment institution have been key advancements, promoted by the constitution of Early Arthritis Clinics (EAC) and the development of more sensitive classification criteria for RA. The outbreak of new COronaVIrus Disease 2019 (COVID-19) has quickly become a global health emergency and has forced a rearrangement in the management of other non-COVID-19 diseases. The impact of the lock-down of the healthcare systems on chronic inflammatory diseases such as RA is expected to be significant but is at present unknown.Objectives:To assess the effects of the lock-down imposed by the COVID-19 pandemic on the referral and clinical presentation of patients with new-onset RA.Methods:Data were retrieved from the Pavia EAC inception cohort, established in 2005 for the early identification of patients with new-onset IA. Referral criteria to the EAC include: ≥3 swollen joints (SJ) and/or <3 SJ and positive squeeze test and/or <3 SJ and morning stiffness >30 min. Demographic and clinical characteristics of the patients are assessed at baseline and regularly over follow-up.At 31 Dec 2020, the Pavia EAC collects information on 2.508 patients. For this study, baseline characteristics of the patients referred in the semester following the COVID-19 lock-down (Jul-Dec 2020) were compared with: (i) patients referred in the semester immediately preceding the lock-down (Jul-Dec 2019); (ii) patients referred in the semester following the publication of the 2010 RA classification criteria (Jan-Jun 2011); (iii) patients referred in the semester preceding the publication of the 2010 criteria (Jul-Dec 2009).Results:In the semester following the lock-down imposed by the COVID-19 pandemic, there was a decrease in the referral of patients with new-onset suspected IA compared with previous periods (n=71 vs n=91 in the semester before the lock-down, n=96 in the first semester of 2011, n=101 in the second semester of 2009). Furthermore, fewer of the referred patients fulfilled RA criteria at presentation (36.6% vs 44.3%, 46.5% and 42.9% in the other semesters). Among patients with RA, more were autoantibody-positive (72% vs 50%, 49.1% and 52.2%). There was a trend for increased diagnostic delay in the overall cohort of RA after the COVID-19 lock-down (Figure 1A). The delay was particularly longer in autoantibody-positive patients, returning to the values seen before the introduction of the 2010 RA criteria (Figure 1B). In contrast, the few autoantibody-negative patients were referred earlier (Figure 1C). Disease activity at presentation was significantly higher in RA patients presenting after the lock-down compared with the progressive trend for reduction observed over the previous years, irrespective of the autoantibody status (Figure 1D-F). Such increase was determined by an inversion of the trend towards lower levels of objective parameters of inflammation, such as the swollen joint count (Figure 1G-I) and acute phase reactants, and a further increase in the secular trend towards worsening of patient-derived measures, such as the tender joint count and patient global assessment (Figure 1J-L).Figure 1.Effects of COVID-19 lock-down on new-onset RA at presentation.Conclusion:The COVID-19 pandemic is posing unprecedented challenges in the management of patients suffering from chronic diseases. RA has returned to be diagnosed outside the window of opportunity, with a significantly higher inflammatory burden at presentation. The many benefits of early diagnosis, which have dramatically changed the outcomes of autoantibody-positive RA, are at risk of vanishing in short times. Equally important, autoantibody-negative RA is at risk of further under-diagnosis and under-treatment.Disclosure of Interests:Bernardo D’Onofrio: None declared, Ludovico De Stefano: None declared, Bianca Lucia Palermo: None declared, Blerina Xoxi: None declared, Antonio Manzo: None declared, Carlomaurizio Montecucco Speakers bureau: BMS, Lilly, Sanofi, Pfizer, Galapagos, Roche, Novartis, Serena Bugatti Speakers bureau: BMS, Lilly, Sanofi, Pfizer, Galapagos

Enhanced treatment strategies and distinct disease outcomes among autoantibody-positive and -negative rheumatoid arthritis patients over 25 years: A longitudinal cohort study in the Netherlands.

Based on different genetic and environmental risk factors and histology, it has been proposed that rheumatoid arthritis (RA) consists of 2 types: autoantibody-positive and autoantibody-negative RA. However, until now, this remained hypothetical. To assess this hypothesis, we studied whether the long-term outcomes differed for these 2 groups of RA patients. In the Leiden Early Arthritis Clinic cohort, 1,285 consecutive RA patients were included between 1993 and 2016 and followed yearly. Treatment protocols in routine care improved over time, irrespective of autoantibody status, and 5 inclusion periods were used as instrumental variables: 1993-1996, delayed mild disease-modifying antirheumatic drug (DMARD) initiation (reference period); 1997-2000, early mild DMARDs; 2001-2005, early methotrexate; 2006-2010, early methotrexate followed by treat-to-target adjustments; 2011-2016, similar to 2006-2010 plus additional efforts for very early referral. Three long-term outcomes were studied: sustained DMARD-free remission (SDFR) (persistent absence of clinical synovitis after DMARD cessation), mortality, and functional disability measured by yearly Health Assessment Questionnaire (HAQ). Treatment response in the short term (disease activity) was measured by Disease Activity Score-28 with erythrocyte sedimentation rate (DAS28-ESR). Linear mixed models and Cox regression were used, stratified for autoantibody positivity, defined as IgG anti-CCP2 and/or IgM rheumatoid factor positivity. In total, 823 patients had autoantibody-positive RA (mean age 55 years, 67% female); 462 patients had autoantibody-negative RA (age 60 years, 64% female). Age, gender, and percentage of autoantibody-positive patients were stable throughout the inclusion periods. Disease activity significantly decreased over time within both groups. SDFR rates increased after introduction of treat-to-target (hazard ratio [HR] 2006-2010 relative to 1993-1996: 3.35 [95% CI 1.46 to 7.72; p = 0.004]; HR 2011-2016: 4.57 [95% CI 1.80 to 11.6; p = 0.001]) in autoantibody-positive RA, but not in autoantibody-negative RA. In autoantibody-positive RA, mortality decreased significantly after the introduction of treat-to-target treatment adjustments (HR 2006-2010: 0.56 [95% CI 0.34 to 0.92; p = 0.023]; HR 2011-2016: 0.33 [95% CI 0.14 to 0.77; p = 0.010]), but not in autoantibody-negative RA (HR 2006-2010: 0.79 [95% CI 0.40 to 1.56; p = 0.50]; HR 2011-2016: 0.36 [95% CI 0.10 to 1.34; p = 0.13]). Similarly, functional disability improved in autoantibody-positive RA for the periods after 2000 relative to 1993-1996 (range -0.16 [95% CI -0.29 to -0.03; p = 0.043] to -0.32 [95% CI -0.44 to -0.20; p < 0.001] units of improvement), but not in autoantibody-negative RA (range 0.10 [95% CI -0.12 to 0.31; p = 0.38] to -0.13 [95% CI -0.34 to 0.07; p = 0.20] units of improvement). Limitations to note were that treatment was not randomized-but it was protocolized and instrumental variable analysis was used to obtain comparable groups-and that a limited spread of ethnicities was included. Although disease activity has improved in both autoantibody-positive and autoantibody-negative RA in recent decades, the response in long-term outcomes differed. We propose that it is time to subdivide RA into autoantibody-positive RA (type 1) and autoantibody-negative RA (type 2), in the hope that this leads to stratified treatment in RA.

Towards stratified treatment of rheumatoid arthritis

Background: To compare the clinical efficacy of different initial treatment strategies in autoantibodynegative rheumatoid arthritis(RA) patients. Methods and findings: Data of the tREACH trial, a stratified single-blinded randomized clinical trial with a treat-to-target strategy, were used. For this analysis, we selected all autoantibodynegative RA patients, defined as fulfillment of 2010-criteria and absence of both rheumatoid factor and anti-citrullinated protein antibody, within the intermediate probability stratum. We compared the following initial treatment strategies in our autoantibody-negative RA population: 25mg methotrexate(iMTX) per week, 400mg hydroxychloroquine(iHCQ) daily or 15mg glucocorticoids(iGCs) orally in a 10-week tapering scheme without any DMARDs. Primary outcome was the proportion of patients with active disease, defined as a disease activity score(DAS)≥2.4, after 3 months of treatment. Secondary outcomes were DAS and functional ability(HAQ) over time using a linear mixed model(LMM), in which we respectively corrected for baseline DAS and HAQ. 116 patients were included and started with iMTX(n=44), iHCQ(n=35) or iGCs(n=37). After 3 months 34%, 34% and 76% of patients respectively treated with iMTX, iHCQ and iGCs had an active disease(p<.0005 for iHCQ and iMTX versus iGCs). Our corrected LMM showed no significant difference in DAS and HAQ over time between the different initial treatment strategies. Conclusions: Initial GCs without csDMARDs are also not indicated for autoantibody-negative RA patients. However, iHCQ and iMTX show similar (early) treatment responses in this subgroup of patients, which suggests that initial treatment can be stratified for autoantibody-negative and autoantibody-positive RA, but validation is needed.

ACPA-negative RA consists of subgroups: patients with high likelihood of achieving sustained DMARD-free remission can be identified by serological markers at disease presentation

BackgroundDisease-modifying antirheumatic drug (DMARD)-free remission, the sustained absence of synovitis after DMARD cessation, is increasingly achievable, especially in autoantibody-negative rheumatoid arthritis (RA). However, underlying mechanisms are unknown and patient subgroups that achieve this outcome are insufficiently characterized. We evaluated whether serological biomarkers at disease onset, as measured within the multi-biomarker disease activity (MBDA) score, are differently expressed in RA patients who achieve sustained DMARD-free remission.MethodsTwo hundred ninety-nine RA patients were evaluated for achievement of sustained DMARD-free remission during a median follow-up of 4.3 years. Twelve biomarkers, as included in the MBDA score, were determined from the serum obtained at disease onset. Patients were categorized as having a low (< 30), moderate (30–44) or high (> 44) score. Analyses were stratified for anti-citrullinated protein antibodies (ACPA) based under the assumption that ACPA-positive and ACPA-negative RA are different disease entities.ResultsTwenty percent achieved sustained DMARD-free remission. Overall, high MBDA scores were associated with achieving DMARD-free remission (high vs. low HR 3.8, 95% CI 1.2–12.2). Among ACPA-negative RA patients, moderate or high scores associated strongly with DMARD-free remission (moderate vs. low HR 9.4, 95% CI 1.2–72.9; high vs. low HR 9.7, 95% CI 1.3–71.1). This association was independent of age and other clinical factors (high vs. low HR 8.2, 95% CI 1.1–61.8). For ACPA-negative RA patients, the biomarkers C-reactive protein, serum amyloid A and matrix metalloproteinase-3 were individually associated with sustained DMARD-free remission. Among ACPA-positive RA patients, scores were not associated with DMARD-free remission.ConclusionsACPA-negative RA patients who achieved sustained DMARD-free remission after treatment withdrawal were characterized by moderate to high MBDA scores at diagnosis. This is the first evidence that ACPA-negative RA can be subdivided in clinically relevant subsets at disease onset using a protein profile.

Latent autoimmunity across disease-specific boundaries in at-risk first-degree relatives of SLE and RA patients.

BackgroundAutoimmune disease prevention requires tools to assess an individual's risk of developing a specific disease. One tool is disease-associated autoantibodies, which accumulate in an asymptomatic preclinical period. However, patients sometimes exhibit autoantibodies associated with a different disease classification. When and how these alternative autoantibodies first appear remain unknown. This cross-sectional study characterizes alternative autoimmunity, and associated genetic and environmental factors, in unaffected first-degree relatives (FDRs) of patients, who exhibit increased future risk for the same disease.MethodsSamples (n = 1321) from disease-specific autoantibody-positive (aAb+) systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes (T1D) patients; and unaffected aAb+ and autoantibody-negative (aAb–) SLE and RA FDRs were tested for SLE, RA, and T1D aAbs, as well as anti-tissue transglutaminase, anti-cardiolipin and anti-thyroperoxidase. FDR SLE and RA genetic risk scores (GRS) were calculated.FindingsAlternative autoimmunity occurred in SLE patients (56%) and FDRs (57·4%), RA patients (32·6%) and FDRs (34·8%), and T1D patients (43%). Expanded autoimmunity, defined as autoantibodies spanning at least two other diseases, occurred in 18·5% of SLE patients, 16·4% of SLE FDRs, 7·8% of RA patients, 5·3% of RA FDRs, and 10·8% of T1D patients. SLE FDRs were more likely to have alternative (odds ratio [OR] 2·44) and expanded (OR 3·27) autoimmunity than RA FDRs. Alternative and expanded autoimmunity were associated with several environmental exposures. Alternative autoimmunity was associated with a higher RA GRS in RA FDRs (OR 1·41), and a higher SLE GRS in aAb+ RA FDRs (OR 1·87), but not in SLE FDRs.InterpretationAutoimmunity commonly crosses disease-specific boundaries in systemic (RA, SLE) and organ-specific (T1D) autoimmune diseases. Alternative autoimmunity is more common in SLE FDRs than RA FDRs, and is influenced by genetic and environmental factors. These findings have substantial implications for preclinical disease pathogenesis and autoimmune disease prevention studies.FundNIH U01AI101981, R01AR051394, U19AI082714, P30AR053483, P30GM103510, U54GM104938, U01AI101934, R01AI024717, U01AI130830, I01BX001834, & U01HG008666.

ACPA IgG galactosylation associates with disease activity in pregnant patients with rheumatoid arthritis

ObjectivesPatients with autoantibody-positive rheumatoid arthritis (RA) are less likely to experience pregnancy-induced improvement of RA disease activity (DAS28-C reactive protein (CRP)) compared with patients with autoantibody-negative RA. Anti-citrullinated protein antibodies...

The 2010 ACR/EULAR criteria are not sufficiently accurate in the early identification of autoantibody-negative rheumatoid arthritis: Results from the Leiden-EAC and ESPOIR cohorts.

The 2010 ACR/EULAR criteria were derived to classify rheumatoid arthritis (RA) earlier in time. Previous studies indeed observed that the 2010 criteria were fulfilled earlier than the 1987 criteria. This study determined whether the 2010 criteria perform equally in early classification of autoantibody-positive and autoantibody-negative RA. From the total Leiden-EAC (n = 3448) and ESPOIR (n = 813) RA patients who fulfilled the 1987 RA criteria at 1 year but not at presentation were selected (n = 463 and n = 53, respectively), as these patients were classified with delay with the 1987 criteria. These RA patients were studied on fulfilling the 2010 criteria at baseline (as 2010 positivity indicated that these RA patients were earlier identified) and these analyses were stratified for patients with and without anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF). Analyses were repeated for DMARD start within the first year as reference for RA (instead of fulfilling the 1987 criteria). In the EAC, 75% of the selected RA patients did already fulfill the 2010 criteria at baseline. In ESPOIR this was 57%, indeed demonstrating early classification with the 2010 criteria. Among the selected autoantibody-positive RA patients of the EAC, 93% was already identified at baseline with the 2010 criteria. Within autoantibody-negative RA this was 51% (p < 0.001), indicating that 49% of autoantibody-negative RA patients were not early classified with the 2010 criteria. Similarly, within autoantibody-positive RA patients in ESPOIR 92% were 2010 positive at baseline, whereas this was only 25% within autoantibody-negative RA (p < 0.001), indicating that 75% of autoantibody-negative RA patients were not early classified with the 2010 criteria. Similar results were obtained when DMARD start was the reference for RA. The 2010 criteria perform well in the early identification of autoantibody-positive RA, but autoantibody-negative RA patients are still frequently missed with these criteria. This implies that other diagnostics are required for ACPA-negative patients.

Association of Fcgamma receptor type 2A and 3A genotypes with rheumatoid arthritis in Chinese population.

SNPs of FcγRs were implicated in pathogenesis of rheumatoid arthritis (RA) and treatment efficacy of TNF inhibitors (TNFi). This study aims to investigate the associations of FcγRIIa and FcγRIIIa genotypes with autoantibody production and treatment response to TNFi in Chinese patients with RA. FcγRIIa and FcγRIIIa polymorphisms were genotyped in 158 RA patients. Response to TNFi was evaluated in 18 patients at 3 and 6 months after treatment. FcγRIIa-131H allele was significantly increased in autoantibody-negative RA patients. FcγRIIa-131H/H+H/R was closely associated with differences in 28-joint disease activity score in patients at months 3 and 6 of TNFi treatment. FcγRIIa-131H allele may have a protective role in autoantibody production and might be a biomarker for predicting good response to TNFi in Chinese RA patients.

How undifferentiated arthritis evolves into chronic arthritis.

Undifferentiated arthritis (UA) is a frequently occurring clinical presentation with a variable outcome. While some forms of UA will spontaneously remit, other forms will progress to chronic arthritis; an outcome that would preferably be prevented. Which immunological factors are normally at the basis of resolution of inflammation, and what, on the other hand, causes inflammation to persist? This review provides an overview of the immunological mechanisms involved in these two scenarios, including specific examples of how these mechanisms apply, or can be influenced in rheumatic diseases. Furthermore, what do we know about risk factors for chronic arthritis, such as the development of autoantibodies? The recent years have provided many insights concerning risk factors for autoantibody-positive versus autoantibody-negative rheumatoid arthritis, which are discussed along with a possible pathophysiological model incorporating autoantibodies into the larger process of disease development. Finally, the evolution of the autoantibody response over time is described.

SPP1 rs9138 variant contributes to the severity of radiological damage in anti-citrullinated protein autoantibody-negative rheumatoid arthritis

ObjectiveWe recently reported an association of the SPP1 rs9138 and rs11439060 functional variants with the risk of rheumatoid arthritis (RA), the association being greater in anti-citrullinated protein autoantibody (ACPA)-negative patients....

THU0008 Meta-analysis of the association of smoking and PTPN22 R620W genotype on autoantibody status and radiological erosions in rheumatoid arthritis

BackgroundSmoking has been linked to production of anti-citrullinated protein antibodies (ACPA) in HLA-DRB1 shared epitope positive patients which has also been associated with a worse severity of rheumatoid arthritis (RA)...

Erratum: Reevaluation of the interaction between HLA-DRB1 shared epitope alleles, PTPN22, and smoking in determining susceptibility to autoantibody-positive and autoantibody-negative rheumatoid arthritis in a large UK Caucasian population

Erratum: Reevaluation of the interaction between HLA-DRB1 shared epitope alleles, PTPN22, and smoking in determining susceptibility to autoantibody-positive and autoantibody-negative rheumatoid arthritis in a large UK Caucasian population

Evaluation of the rheumatoid arthritis susceptibility loci HLA-DRB1, PTPN22, OLIG3/TNFAIP3, STAT4 and TRAF1/C5 in an inception cohort.

IntroductionThis study investigated five confirmed rheumatoid arthritis (RA) susceptibility genes/loci (HLA-DRB1, PTPN22, STAT4, OLIG3/TNFAIP3 and TRAF1/C5) for association with susceptibility and severity in an inception cohort.MethodsThe magnitude of association for each genotype was assessed in 1,046 RA subjects from the Yorkshire Early RA cohort and in 5,968 healthy UK controls. Additional exploratory subanalyses were undertaken in subgroups defined by autoantibody status (rheumatoid factor and anti-cyclic citrullinated peptide) or disease severity (baseline articular erosions, Health Assessment Questionnaire (HAQ) score and swollen joint count (SJC)).ResultsIn the total RA inception cohort, the HLA-DRB1 shared epitope (per-allele odds ratio (OR) = 2.1, trend P < 0.0001), PTPN22 (per-allele OR = 1.5, trend P < 0.0001), OLIG3/TNFAIP3 locus (per-allele OR = 1.2, trend P = 0.009) and TRAF1/C5 locus (per-allele OR = 1.1, trend P = 0.04) were associated with RA. The magnitude of association for these loci was increased in those patients who were autoantibody-positive. PTPN22 was associated with autoantibody-negative RA (per-allele OR = 1.3, trend P = 0.04). There was no evidence of association between these five genetic loci and baseline erosions or SJC in the total RA cohort, after adjustment for symptom duration. TRAF1/C5 was significantly associated with baseline HAQ, however, following adjustment for symptom duration (P trend = 0.03).ConclusionsThese findings support the mounting evidence that different genetic loci are associated with autoantibody-positive and autoantibody-negative RA, possibly suggesting that many of the genes identified to date are associated with autoantibody production. Additional studies with a specific focus on autoantibody-negative RA will be needed to identify the genes predisposing to this RA subgroup. The TRAF1/C5 locus in particular warrants further investigation in RA as a potential disease severity locus.