Preclinical Phase Of Rheumatoid Arthritis Research Articles

OA03 Developing a multivariable prediction model to identify anti-CCP positive individuals among those with non-specific musculoskeletal symptoms in primary care

Abstract Background/Aims A phase of immunologically imminent rheumatoid arthritis (RA) precedes the onset of clinical RA, characterised by increased circulating anti-cyclic citrullinated peptide (anti-CCP) antibodies. Early identification in the pre-clinical phase of RA in primary care (PC), through targeted anti-CCP testing, could prompt secondary care referral for earlier diagnosis, achieving better long-term outcomes. This study aimed to develop a model identifying those likely to be anti-CCP positive amongst people presenting to PC with non-specific musculoskeletal symptoms. Methods Participants were recruited across the UK between 2014 and 2020 to the Leeds ‘Co-ordinated Programme to Prevent Arthritis’, a prospective, observational cohort study. Participants were aged ≥18 years who presented to PC with non-specific musculoskeletal symptoms and no history of clinical synovitis. Fifteen baseline predictors were considered: age; gender; smoking status; first degree relative (FDR) with RA; and patient reported pain in: neck; back; shoulders; elbows; hips; wrists; thumbs; hand and/or fingers; knees; ankles; foot and/or toes. Participants were followed up at 12 months to determine if they had developed RA. Analysis was performed in R. Variable selection was carried out via LASSO logistic regression. Model performance was assessed using area under the receiver operating characteristic curve (ROC AUC); decision curve analysis was utilised to assess clinical utility. Internal validation was carried out via 200 bootstrap re-samples with replacement to estimate corrected model fit estimates. Results Analysis included 6,879 participants; 203 (2.95%) anti-CCP positive. Thirteen predictors were retained (age and ankles omitted); scores for each predictor were: sex (male) [+3], FDR with RA [+3], smoking (ever) [+2], pain in back [-3], neck [-2], knee [-1], wrist [+4], foot/toes [+3], hand/fingers [+3], shoulder [+3], thumb [+1]. With a score of ≥ 11 (≥4% risk) for anti-CCP testing, the ROC AUC was 0.65 (95% CI [0.61-0.69], corrected AUC=0.49). Choosing a threshold of 4% suggested that the benefit of testing one anti-CCP positive patient is 24 times larger than the harm of testing one anti-CCP negative patient. Sensitivity and specificity were 38.42 and 81.88 and positive- and negative-predicted values were 6.06 and 97.76. The net benefit was 0.0040 (corrected=0.0026). This threshold resulted in 19% being tested, corresponding to 39% of all anti-CCP positive participants. 12 month follow-up data were available for 2,480 participants. Out of those who would be tested using our model, 6.68% developed RA, compared with 1.94% if everyone was tested. Out of those tested who were anti-CCP positive, 56.85% developed RA (amongst those tested who were anti-CCP negative, 1.23% developed RA). Conclusion Targeted use of anti-CCP testing in PC may prompt earlier identification of people at risk of RA. Interviews with PC clinicians are currently being undertaken to understand the key behaviours required to support clinicians using this prediction model, alongside heath economic modelling to explore potential cost-effectiveness. Disclosure H.J. Siddle: Grants/research support; HJS has received funding from HEE/NIHR for this research [ICA-SCL-2018-04-ST2-004]. M. Wilson: None. J.L. Nam: None. L. Garcia-Montoya: None. L. Duquenne: None. K. Mankia: Consultancies; Serac Lifesciences. Honoraria; Galapagos, Lilly, Abbvie. Grants/research support; Eli Lilly, Gilead. Other; Attending meetings/travel: Abbvie. P. Emery: Consultancies; Lilly, Galapagos. Honoraria; Novartis, Lilly, Abbvie, Gilead, Galapagos. Grants/research support; Lilly, Samsung. Other; Advisory Board: Lilly, Astra Zeneca, BMS. E.M.A. Hensor: Grants/research support; Institution level grant for the NIHR Leeds Biomedical Research Centre.

Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial

Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of developing rheumatoid arthritis. In the arthritis prevention in the pre-clinical phase of rheumatoid arthritis with abatacept (APIPPRA) trial, we aimed to evaluate the feasibility, efficacy, and acceptability of treating high risk individuals with the T-cell co-stimulation modulator abatacept. The APIPPRA study was a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial done in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands. Participants (aged ≥18 years) at risk of rheumatoid arthritis positive for ACPA and rheumatoid factor with inflammatory joint pain were recruited. Exclusion criteria included previous episodes of clinical synovitis and previous use of corticosteroids or disease-modifying antirheumatic drugs. Participants were randomly assigned (1:1) using a computer-generated permuted block randomisation (block sizes of 2 and 4) stratified by sex, smoking, and country, to 125 mg abatacept subcutaneous injections weekly or placebo for 12 months, and then followed up for 12 months. Masking was achieved by providing four kits (identical in appearance and packaging) with pre-filled syringes with coded labels of abatacept or placebo every 3 months. The primary endpoint was the time to development of clinical synovitis in three or more joints or rheumatoid arthritis according to American College of Rheumatology and European Alliance of Associations for Rheumatology 2010 criteria, whichever was met first. Synovitis was confirmed by ultrasonography. Follow-up was completed on Jan 13, 2021. All participants meeting the intention-to-treat principle were included in the analysis. This trial was registered with EudraCT (2013-003413-18). Between Dec 22, 2014, and Jan 14, 2019, 280 individuals were evaluated for eligibility and, of 213 participants, 110 were randomly assigned to abatacept and 103 to placebo. During the treatment period, seven (6%) of 110 participants in the abatacept group and 30 (29%) of 103 participants in the placebo group met the primary endpoint. At 24 months, 27 (25%) of 110 participants in the abatacept group had progressed to rheumatoid arthritis, compared with 38 (37%) of 103 in the placebo group. The estimated proportion of participants remaining arthritis-free at 12 months was 92·8% (SE 2·6) in the abatacept group and 69·2% (4·7) in the placebo group. Kaplan-Meier arthritis-free survival plots over 24 months favoured abatacept (log-rank test p=0·044). The difference in restricted mean survival time between groups was 53 days (95% CI 28-78; p<0·0001) at 12 months and 99 days (95% CI 38-161; p=0·0016) at 24 months in favour of abatacept. During treatment, abatacept was associated with improvements in pain scores, functional wellbeing, and quality-of-life measurements, as well as low scores of subclinical synovitis by ultrasonography, compared with placebo. However, the effects were not sustained at 24 months. Seven serious adverse events occurred in the abatacept group and 11 in the placebo group, including one death in each group deemed unrelated to treatment. Therapeutic intervention during the at-risk phase of rheumatoid arthritis is feasible, with acceptable safety profiles. T-cell co-stimulation modulation with abatacept for 12 months reduces progression to rheumatoid arthritis, with evidence of sustained efficacy beyond the treatment period, and with no new safety signals. Bristol Myers Squibb.

The pre-clinical phase of rheumatoid arthritis: From risk factors to prevention of arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease considered as a multistep process spanning from the interaction of genetic (e.g., shared epitope or non-HLA loci), environmental and behavioral risk factors (e.g., smoking) leading to breaking immune tolerance and autoimmune processes such as the production of autoantibodies (e.g., antibodies against citrullinated proteins ACPA or rheumatoid factors, RF), development of the first symptoms without clinical arthritis, and, finally, the manifestation of arthritis. Despite the typical joint involvement in established RA, the pathogenesis of the disease likely begins far from joint structures: in the lungs or periodontium in association with citrullination, intestinal microbiome, or adipose tissue, which supports normal findings in synovial tissue in ACPA+ patients with arthralgia. The presence of ACPA is detectable even years before the first manifestation of RA. The pre-clinical phase of RA is the period preceding clinically apparent RA with ACPA contributing to the symptoms without subclinical inflammation. While the combination of ACPA and RF increases the risk of progression to RA by up to 10 times, increasing numbers of novel autoantibodies are to be investigated to contribute to the increased risk and pathogenesis of RA. With growing knowledge about the course of RA, new aspiration emerges to cure and even prevent RA, shifting the "window of opportunity" to the pre-clinical phases of RA. The clinical definition of individuals at risk of developing RA (clinically suspect arthralgia, CSA) makes it possible to unify these at-risk individuals' clinical characteristics for "preventive" treatment in ongoing clinical trials using mostly biological or conventional synthetic disease-modifying drugs. However, the combination of symptoms, laboratory, and imaging biomarkers may be the best approach to select the correct target at-risk population. The current review aims to explore different phases of RA and discuss the potential of (non)pharmacological intervention aiming to prevent RA.

High miR-451 expression in peripheral blood mononuclear cells from subjects at risk of developing rheumatoid arthritis

Individuals carrying anti-citrullinated protein antibodies (ACPA) are considered at high risk of developing rheumatoid arthritis (RA). The altered expression of miRNAs contributes to the pathogenesis of RA. We aimed to identify differentially expressed miRNAs in the peripheral blood of ACPA-positive individuals with arthralgia at risk of RA compared to healthy controls (HC) and to determine their implications in the preclinical phase of RA. A comprehensive analysis of miRNAs revealed the dysregulation of miR-451 in peripheral blood mononuclear cells (PBMC) and plasma from RA-risk individuals. Higher miR-451 expression in PBMC from RA-risk individuals was further validated. Notably, miR-451 was previously shown to regulate CXCL16, a protein involved in RA pathogenesis. The expression of miR-451 in PBMC positively correlated with the CXCL16 mRNA, which could be secondary to the inflammation-induced expression of miR-451. Transfection of monocytes with pre-miR-451 in vitro resulted in the downregulation of CXCL16. Moreover, flow cytometry revealed a lower count of CXCL16-positive monocytes in RA-risk individuals. We propose that the constitutive or inflammation-induced upregulation of miR-451 in PBMC downregulates the expression of CXCL16, reduces the inflammatory milieu and thereby strives to delay the shift from the preclinical phase to the clinical manifestation of RA. This hypothesis warrants further investigation.

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.

Subclinical inflammation in the preclinical phase of rheumatoid arthritis might contribute to articular joint damage

The first degree relatives of rheumatoid arthritis (RA) patients have a higher risk of developing RA, which is related to the expression of autoantibodies against citrullinated proteins (ACPA). Remarkably, prior to the onset of RA, cartilage damage is already initiated, whereas ACPA autoantibodies are already expressed. Here we show that both TNF-α and IL-6 are also increased prior to the onset of RA. Furthermore, when the levels of DKK1 and Sclerostin were evaluated in first degree relatives of RA patients, we found that the serum levels of TNF- α correlate with the expression levels of both DKK1 and Sclerostin. Interestingly, when the disease is already established, the correlation of TNF- α with DKK1 is lost in RA patients, whereas the correlation of Sclerostin with both TNF- α and IL-6 is further increased. Our data suggest a subclinical inflammation in patients at high risk of developing RA, which might lead to an increase in the levels of both DKK1 and Sclerostin, contributing to joint damage in the preclinical phase of the disease linked to the expression of ACPA autoantibodies.

Diagnostic Role of Survivin in Rheumatoid Arthritis: A Systematic Review.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, which is characterized by the hyperplasia of synovial tissue. Survivin is a member of the inhibitor of apoptosis protein family, which facilitates the formation of functional T-cell receptor and differentiation of memory T cells. Survivin plays an important role in the expression of major histocompatibility complex molecules and mature dendritic cells, which play the main role in the etiology of RA. This systematic review was conducted to investigate the evidence on the role of survivin as a diagnostic and predictive value in RA patients. All published articles related to the subject of interest and published up to 30 March 2018 were searched in three databases, including Google Scholar, PubMed, and Web of Science. After a detailed evaluation of the full-text version of the papers, 23 articles were entered into the study. The elevation of survivin in the preclinical phase of RA and its association with anti-cyclic citrullinated peptide (CCP) antibodies suggested it as a predictor of RA. Recently, survivin has been introduced as the biomarker of joint damage and poor response to antirheumatic treatment in RA patients. Based on the evidence, survivin level had high specificity and sensitivity in the diagnosis of RA patients. The results of the reviewed studies demonstrated that a positive survivin level was associated with the presence of anti-CCP antibodies.

Arthritis prevention in the pre-clinical phase of RA with abatacept (the APIPPRA study): a multi-centre, randomised, double-blind, parallel-group, placebo-controlled clinical trial protocol

Trial designWe present a study protocol for a multi-centre, randomised, double-blind, parallel-group, placebo-controlled trial that seeks to test the feasibility, acceptability and effectiveness of a 52-week period of treatment with the first-in-class co-stimulatory blocker abatacept for preventing or delaying the onset of inflammatory arthritis.MethodsThe study aimed to recruit 206 male or female subjects from the secondary care hospital setting across the UK and the Netherlands. Participants who were at least 18 years old, who reported inflammatory sounding joint pain (clinically suspicious arthralgia) and who were found to be positive for serum autoantibodies associated with rheumatoid arthritis (RA) were eligible for enrolment. All study subjects were randomly assigned to receive weekly injections of investigational medicinal product, either abatacept or placebo treatment over the course of a 52-week period. Participants were followed up for a further 52 weeks. The primary endpoint was defined as the time to development of at least three swollen joints or to the fulfilment of the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for RA using swollen but not tender joints, whichever endpoint was met first. In either case, swollen joints were confirmed by ultrasonography. Participants, care givers, and those assessing the outcomes were all blinded to group assignment. Clinical assessors and ultrasonographers were also blinded to each other’s assessments for the duration of the study.ConclusionsThere is limited experience of the design and implementation of trials for the prevention of inflammatory joint diseases. We discuss the rationale behind choice and duration of treatment and the challenges associated with defining the “at risk” state and offer pragmatic solutions in the protocol to enrolling subjects at risk of RA.Trial registrationCurrent Controlled Trials, ID: ISRCTN46017566. Registered on 4 July 2014.

Accelerated onset of arthritis by systemic infection of Mycoplasma fermentans in the knock-in mice gp130F759

Abstract Development of autoimmune diseases is influenced by both genetic and environmental factors. The knock-in mouse gp130F759 having a point mutation Y759F in gp130, a signaling receptor subunit for IL-6 family cytokines, spontaneously develops arthritis like rheumatoid arthritis (RA) at 8 months old (M.O.) by aberrant IL-6 signals. Mycoplasma fermentans (Mf) was reported to exist in the synovial fluid of RA, but its pathogenic role has not been clarified. In this study, we examined the effects of systemic infection with Mf on the arthritis of gp130F759, and the cellular changes in the synovium. Gp130F759 at 3 M.O. with no symptoms of arthritis were infected with Mf via vein. The clinical scores based on the restriction of joint flexibility were determined from day 3 to 28 after infection. At 1 month after infection, the group with Mf infection had significantly higher total scores of 4 limbs than the group at the same age without infection. Additionally, the cellular populations and numbers in the synovium were analyzed with flowcytometry. The kinetics study revealed that the numbers of the synovial cells predominated by neutrophils increased at day 10 and 28 after infection. To verify the roles for neutrophils increased, 0.25 mg of anti-Gr-1 antibody was injected intraperitoneally at 9 days after infection. The group of treated mice showed no increases of the clinical scores and the synovial cells at 1 month after infection. These data indicated that systemic infection of Mf induces neutrophil-dependent facilitation of arthritis in gp130F759. We propose that this model is useful to clarify the molecular events caused by microorganisms at the preclinical phase of RA.

Both Systemic and Intra-articular Immunization with Citrullinated Peptides Are Needed to Induce Arthritis in the Macaque

Anti-citrullinated peptides antibodies (ACPAs) have high specificity for the diagnosis of rheumatoid arthritis (RA), but their role in the pathophysiology is not fully established. The main genetic risk factor for RA, the shared epitope in major histocompatibility complex class II, is associated with ACPAs. Among certain non-human primates, 8% carry the shared epitope called H6 haplotype, and being similar to humans, are ideal candidates to study the role of ACPAs in RA. The goal of this study was to develop a macaque model of RA based on immunization against citrullinated peptides to generate an ACPA-mediated model of arthritis. Cynomolgus macaques were immunized with four citrullinated peptides from vimentin, fibrinogen, and aggrecan, known to induce T-cell response in RA patients, and received an intra-articular (IA) boost with the same four citrullinated peptides pooled. In the macaque, the T-cell response was specific to citrullinated peptides. Antibodies generated in response to immunization were cross-reactive between the citrulline and arginine peptides. The presence of the H6 haplotype did not affect the magnitude of the immune response. Since no clinical response was observed, macaques received an IA boost with the same four peptides pooled and incomplete Freund's adjuvant, which led to a prolonged neutrophil-rich mono-arthritis, preferentially in H6-positive animals. Conversely, animals boosted with incomplete Freund's adjuvant alone presented only transient mono-arthritis. This two-hit model of prolonged mono-arthritis mimics what could happen in RA. Despite the limited number of joints with disease in the macaque model, the model appears unique to study the events occurring during the preclinical phase of RA, from immunization against citrullinated peptides to the clinical appearance of disease.

La polyarthrite rhumatoïde : une physiopathologie mieux connue ?

Improvement of rheumatoid arthritis (RA) management requires a better understanding of the sequence of events leading to the development of clinically detectable RA and perhaps the identification of the etiological factors, which are probably numerous. These objectives are being pursued in studies of preclinical RA. The literature review presented herein indicates that the immunological conflict probably originates outside the joints, at mucous membrane sites and, more specifically, in the upper airways and digestive tractus. The preclinical phase of RA can last for many years, then, in individuals at risk, an immunological conflict develops then spins out of control, causing increases in autoantibody titers and subsequently in levels of serum markers for inflammation, before the development of the first joint symptoms. Improved knowledge of the preclinical phase, together with information from genetic markers, should allow the identification of profiles associated with susceptibility to RA and, in the future, the development of preventive strategies. For that purpose, fine tuning immunometabolism could an interesting to chemotherapy or overt immunosuppression to prevent RA clinical development.

Preventive Treatments for Rheumatoid Arthritis: Issues Regarding Patient Preferences

The detection of biomarkers in the preclinical phase of rheumatoid arthritis (RA) and recent therapeutic advances suggest that it may be possible to identify and treat persons at high risk and to prevent the development of RA. Several trials are ongoing to test the efficacy of a therapeutic intervention in primary prevention. This paper reviews potential populations that might be considered for preventative medication. Further, we review the medications that are being explored to treat individuals considered at high risk of developing RA. Finally, in a group of asymptomatic individuals at high risk of developing RA, we assessed which factors mattered most when considering a preventive therapeutic intervention and what type of preventive treatment would be most acceptable to them. Understanding subjects' perceptions of risks and benefits and willingness to undergo preventive therapy will be important in designing and implementing screening and preventive strategies.

Early microbial changes affect mucosal immunity in autoimmune arthritis

Abstract Multiple lines of evidence now suggest that autoimmune disease may result from microbial-mucosal interactions. Microbial dysbiosis occurs in new onset seropositive rheumatoid arthritis (RA); and during the preclinical phase of RA, there is an expansion of mucosal autoantibodies and plasmablasts. These findings strongly suggest that a mucosal site may drive the initial break in tolerance that leads to RA. Using the murine collagen-induced arthritis model of RA, we find that microbiome diversity changes quickly after immunization with bovine type II collagen, at the time when disease-related autoantibodies develop, but before clinical CIA is evident. Significant alterations in taxa clustered in Clostridia families occur in CIA. Interestingly, using IgA-seq in human at-risk for RA study groups we find that those subjects with autoantibodies have similar alterations in Clostridia families. Furthermore, during the development of murine CIA, increased intestinal permeability and altered cytokine profiles paralleled disease development and microbiota alterations. Taken together, these data suggest a model in which early microbial alterations stimulate mucosal immune responses that drive the development of pathogenic autoantibodies. Future studies are aimed at identifying specific bacterial species and elucidating the pathway by which they stimulate autoantibody production.

AB0149 Identification and Characterization of A Synovial Fluid Microbial DNA in Rheumatoid Arthritis Patients

BackgroundThe preclinical phase of Rheumatoid Arthritis (RA) is characterized by an immunological disorder that predate the arthritis onset for several years, and is supposed to take birth in oral, respiratory...

FRI0339 Patterns of Isotype Distribution in Circulating Antibodies in the Pre-Clinical Phase of Rheumatoid Arthritis and their Relation to Smoking

BackgroundPrevious studies indicate that several different isotypes of circulating anti-citrullinated peptide antibodies (ACPAs) and rheumatoid factors (RF) can be detected in individuals who later develop rheumatoid arthritis (RA) years before...

OP0172 Characterising Arthralgia in the Preclinical Phase of Rheumatoid Arthritis Using Magnetic Resonance Imaging

BackgroundThe phase of arthralgia is the earliest moment to clinically recognize patients who will develop Rheumatoid Arthritis (RA). Previous imaging studies in the phase of arthralgia without clinical arthritis showed...

AB0343 Description of Pulmonary Dysfunction in Early Rheumatoid Arthritis

BackgroundSeveral environmental factors were found to be associated with rheumatoid arthritis (RA), such as tobacco, silica, or atmospheric pollutants. These factors are characterized by a first contact with the respiratory...

Review: The Preclinical Phase of Rheumatoid Arthritis: What Is Acknowledged and What Needs to be Assessed?

Review: The Preclinical Phase of Rheumatoid Arthritis: What Is Acknowledged and What Needs to be Assessed?

OP0084 Patterns of circulating antibodies in the pre-clinical phase of rheumatoid arthritis suggest epitope spreading in the immune reaction against citrullinated peptides

BackgroundPrevious studies indicate that anti-citrullinated peptide antibodies (ACPAs) may be detected in individuals who later develop rheumatoid arthritis (RA) years before onset, and that smoking is a predictor of RA.ObjectivesTo...

OP0020 Validation of gene signatures to predict rheumatoid arthritis development

BackgroundEarly recognition of development of rheumatoid arthritis (RA) allows timely start of treatment. It is known that antibodies against citrullinated proteins (ACPA) and rheumatoid factor (RF) have a predictive value...