Clinically Suspect Arthralgia Research Articles

Predictors of quality of life, functional status, depression and fatigue in early arthritis: comparison between clinically suspect arthralgia, unclassified arthritis and rheumatoid arthritis

BackgroundRheumatoid arthritis (RA) is often preceded by symptomatic phases during which classification criteria are not fulfilled. The health burden of these “at-risk” stages is not well described. This study assessed health-related quality of life (HRQoL), function, fatigue and depression in newly presenting patients with clinically suspect arthralgia (CSA), unclassified arthritis (UA) or RA.MethodsCross-sectional analysis of baseline Patient-Reported Outcome Measures (PROMs) was conducted in patients from the Birmingham Early Arthritis Cohort. HRQoL, function, depression and fatigue at presentation were assessed using EQ-5D, HAQ-DI, PHQ-9 and FACIT-F. PROMs were compared across CSA, UA and RA and with population averages from the HSE with descriptive statistics. Multivariate linear regression assessed associations between PROMs and clinical and sociodemographic variables.ResultsOf 838 patients included in the analysis, 484 had RA, 200 had CSA and 154 had UA. Patients with RA reported worse outcomes for all PROMs than those with CSA or UA. However, “mean EQ-5D utilities were 0.65 (95%CI: 0.61 to 0.69) in CSA, 0.61 (0.56 to 0.66) in UA and 0.47 (0.44 to 0.50) in RA, which was lower than in general and older (≥ 65 years) background populations.” In patients with CSA or UA, HRQoL was comparable to chronic conditions such as heart failure, severe COPD or mild angina. Higher BMI and older age (≥ 60 years) predicted worse depression (PHQ-9: -2.47 (-3.85 to -1.09), P < 0.001) and fatigue (FACIT-F: 5.05 (2.37 to 7.73), P < 0.001). Women were more likely to report worse function (HAQ-DI: 0.13 (0.03 to 0.21), P = 0.01) and fatigue (FACIT-F: -3.64 (-5.59 to -1.70), P < 0.001), and residents of more deprived areas experienced decreased function (HAQ-DI: 0.23 (0.10 to 0.36), P = 0.001), greater depression (PHQ-9: 1.89 (0.59 to 3.18), P = 0.004) and fatigue (FACIT-F: -2.60 (-5.11 to 0.09), P = 0.04). After adjustments for confounding factors, diagnostic category was not associated with PROMs, but disease activity and polypharmacy were associated with poorer performance across all PROMs.ConclusionsPatient-reported outcomes were associated with disease activity and sociodemographic characteristics. Patients presenting with RA reported a higher health burden than those with CSA or UA, however HRQoL in the pre-RA groups was significantly lower than population averages.

Patient burden and joint-inflammation during development of RA from arthralgia: is it similar in ACPA-positive and ACPA-negative disease?

Anti-citrullinated protein antibody(ACPA)-positive and ACPA-negative rheumatoid arthritis(RA) differ in underlying risk factors but have a similar clinical presentation at RA-diagnosis. It is unknown what the ACPA-associated differences or similarities are during the symptomatic at-risk stage of RA, clinically suspect arthralgia(CSA). To deepen insights into these differences/similarities, we compared the course of symptoms/impairments and subclinical joint-inflammation in the CSA-phase during progression to inflammatory arthritis(IA) or to CSA-resolution. 845 CSA-patients were followed for median 24 months; 136 patients developed IA and additional 355/505 patients had resolution of CSA according to rheumatologists. Patient burden (pain/morning stiffness/fatigue/functional disabilities/presenteeism) was assessed at baseline, 4/12/24 months and IA-development. Subclinical joint-inflammation in hands/feet was assessed over time with 1.5 T-MRI. Linear/Poisson mixed models were used. Both in ACPA-positive and ACPA-negative patients, patient burden increased towards IA-development and decreased towards CSA-resolution. However, patient burden was lower in ACPA-positive than ACPA-negative disease on all timepoints. Conversely, subclinical joint-inflammation tended to increase more rapidly during development of ACPA-positive IA (IRR = 1.52,95%CI = 0.94-2.47, p= 0.089), and remained higher over time in ACPA-positive CSA-patients achieving resolution compared with ACPA-negative patients (IRR = 1.52,95%CI = 1.07-2.15, p= 0.018). Although correlation coefficients between changes in patient burden and subclinical joint-inflammation during progression to IA were weak, they were consistently higher in ACPA-positive than ACPA-negative disease, e.g. ρ = 0.29 vs ρ = 0.12 for functional disabilities. During RA-development and CSA-resolution, ACPA-positive CSA-patients have lower patient burden, but more subclinical joint-inflammation than ACPA-negative CSA-patients. These data strengthen the notion that the development of ACPA-positive and ACPA-negative RA is pathophysiologically different, and encourage further research on these differences.

When does obesity exert its effect in conferring risk of developing RA: a large study in cohorts of symptomatic persons at risk

ObjectivesObesity is a known risk factor for developing rheumatoid arthritis (RA). However, it is unclear whether obesity exerts its risk effect during the asymptomatic or the symptomatic clinically suspect arthralgia...

Patient-reported swelling in arthralgia patients at risk for rheumatoid arthritis: is it of value?

Patients with Clinically Suspect Arthralgia (CSA) are at risk for developing Rheumatoid Arthritis (RA). These patients often report joint swelling while this is not objectified by physical examination. To explore the value of patient-reported swelling in CSA, we aimed to determine its association with subclinical joint-inflammation on imaging and RA-development. In two independent, similarly designed CSA-cohorts from the Netherlands, symptomatic patients at risk for RA were studied. At baseline, patients indicated whether they had experienced swelling in hand joints. Subclinical joint-inflammation was assessed with MRI or ultrasound (US). Patients were followed for inflammatory arthritis development. In total, 534 CSA-patients from two independent cohorts were studied, patient-reported swelling was present in 57% in cohort 1, and in 43% in cohort 2. In both cohorts patient-reported swelling was associated with subclinical joint-inflammation. Using MRI, it associated specifically with tenosynovitis (OR 3.7 (95%CI 2.0-6.9)) and when using US with synovitis (OR 2.3 (95%CI 1.04-5.3)). CSA-patients with self-reported swelling at baseline developed arthritis more often, with hazard ratios of 3.7 (95%CI 2.0-6.9) and 3.4 (95%CI 1.4-8.4) in cohort 1 and 2, respectively. This was independent of clinical predictors (e.g. morning stiffness), autoantibody-positivity and US-detected subclinical joint-inflammation. However, when corrected for MRI-detected subclinical joint-inflammation, self-reported swelling was no longer an independent predictor. Patient-reported joint swelling in CSA relates to subclinical joint-inflammation and is an independent risk factor for RA-development, but it is less predictive than the presence of MRI-detected subclinical joint-inflammation.

To treat or not to treat? Current attitudes on treatment aimed at modifying the disease burden in clinically suspect arthralgia: a survey among participants of the TREAT EARLIER trial and healthcare professionals

ObjectivesWhile awaiting therapies accomplishing rheumatoid arthritis (RA)-prevention in individuals at-risk, recent evidence supports that a 1-year methotrexate treatment may lead to sustained reduction in disease burden and subclinical joint inflammation...

The Natural Sequence in Which Subclinical Inflamed Joint Tissues Subside or Progress to Rheumatoid Arthritis: A Study of Serial MRIs in the TREAT EARLIER Trial.

The natural trajectory of clinical arthritis progression at the tissue level remains elusive. We hypothesized that subclinical inflammation in different joint tissues (synovitis, tenosynovitis, osteitis) increases in a distinct temporal order in patients with clinically suspect arthralgia (CSA) who develop rheumatoid arthritis (RA) and subsides in a different sequence when CSA spontaneously resolves. We studied 185 serial magnetic resonance images (MRIs) from CSA patients with subclinical joint inflammation from the placebo arm of the TREAT EARLIER trial: 52 MRIs from 21 RA progressors (MRIs conducted at 1 year before, at 4 months before, and upon RA development), and 133 MRIs from 35 patients with spontaneous resolution of pain (MRIs conducted at baseline and at 4, 12, and 24 months). MRIs were scored for osteitis, synovitis, and tenosynovitis. We used cross-lagged models to evaluate 2 types of time patterns between pairs of inflamed tissues: a simultaneous pattern (coinciding changes) and a subsequent pattern (inflammatory changes in 1 tissue preceding changes in another tissue). In patients who developed RA, synovitis, tenosynovitis, and osteitis increased simultaneously. Increasing osteitis occurred in the final 4 months before RA diagnosis, following incremental tenosynovitis and synovitis changes during the 1 year to 4 months before diagnosis (P < 0.01). In anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative patients who progressed to RA, osteitis increased just before RA development. In patients with pain resolution, simultaneous decreases in synovitis, tenosynovitis, and osteitis occurred, with tenosynovitis decreasing in the first 4 months after CSA onset preceding decreasing synovitis and osteitis during 4-12 months (P = 0.02 and P < 0.01). We identified natural sequences of subclinical inflammation in different joint tissues, which deepens our understanding of clinical arthritis and RA development. During RA progression, increasing osteitis followed previous increases in tenosynovitis and synovitis. During pain resolution, tenosynovitis decreased first, followed by decreasing synovitis and osteitis.

The course of cytokine and chemokine gene expression in clinically suspect arthralgia patients during progression to inflammatory arthritis.

Autoantibody responses increase years before the onset of inflammatory arthritis (IA) and are stable during transitioning from clinically suspect arthralgia (CSA) to IA. Cytokine and chemokine levels also increase years before IA onset. However, the course in the at-risk stage of CSA during progression to disease or non-progression is unknown. To increase the understanding of processes mediating disease development, we studied the course of cytokine, chemokine and related receptors gene expression in CSA patients during progression to IA and in CSA patients who ultimately did not develop IA. Whole-blood RNA expression of 37 inflammatory cytokines, chemokines and related receptors was determined by dual-colour reverse transcription multiplex ligation-dependent probe amplification in paired samples of CSA patients at CSA onset and either at IA development or after 24 months without IA development. ACPA-positive and ACPA-negative CSA patients developing IA were compared at CSA onset and during progression to IA. Generalised estimating equations tested changes over time. A false discovery rate approach was applied. None of the cytokine/chemokine genes significantly changed in expression between CSA onset and IA development. In CSA patients without IA development, G-CSF expression decreased (P = 0.001), whereas CCR6 and TNIP1 expression increased (P < 0.001 and P = 0.002, respectively) over a 2 year period. Expression levels in ACPA-positive and ACPA-negative CSA patients who developed IA were similar. Whole-blood gene expression of assessed cytokines, chemokines and related receptors did not change significantly from CSA to IA development. This suggests that changes in expression of these molecules may not be related to the final process of developing chronicity and may have occurred preceding CSA onset. Changes in gene expression in CSA patients without IA development may provide clues for processes related to resolution.

Joint involvement in RA starts predominantly in the hands: functional, clinical and imaging studies in clinically suspect arthralgia and during progression to RA

ObjectivesIt is unknown whether rheumatoid arthritis (RA) starts in hands or feet. To investigate this, we performed functional, clinical and imaging studies during progression from clinically suspect arthralgia (CSA) to...

OA04 Association of clinical and demographic factors with quality of life, functional status, depression, and fatigue in patients presenting with, and at risk of, rheumatoid arthritis

Abstract Background/Aims Rheumatoid arthritis (RA) is often preceded by symptomatic phases during which classification criteria are not fulfilled. The health burden of these “at-risk” stages is not well described. This study assessed health-related quality of life (HRQoL), functioning, fatigue and depression in newly presenting patients with clinically suspect arthralgia (CSA), unclassified arthritis (UA) and RA. Methods Cross-sectional analysis of baseline Patient-Reported Outcome Measures (PROMs) was conducted in 838 patients with CSA, UA or RA recruited to the Birmingham Early Arthritis Cohort. HRQoL, function, depression and fatigue at presentation were assessed using EQ-5D, HAQ-DI, PHQ-9 and FACIT-F, respectively. Descriptive statistics and multivariate linear regression were performed to assess associations between clinical/demographic variables and PROMs. Results Patients with RA at initial presentation had worse PROMs than those with CSA or UA. However, HRQoL was decreased in all groups. In patients with CSA/UA, HRQoL was comparable to data relating to chronic conditions such as heart failure, severe COPD or mild angina from the Health Survey for England (HSE). Associations between predictor variables and PROMs are summarised in Table 1. Increased functional disability was associated with female sex, older age, obesity, lower quintiles of social deprivation, increased disease activity and polypharmacy. HRQoL was associated with increased disease activity and polypharmacy. The severity of depression (PHQ-9) increased with older age, increasing BMI, living in areas with the lowest quintile of social deprivation, increased disease activity and polypharmacy. Fatigue (FACIT-F) was associated with female sex, increasing BMI, disease activity and polypharmacy. After adjusting for the demographic and clinical factors, the diagnosis assigned at baseline did not affect any of the studied PROMs, but disease activity and polypharmacy were strongly linked to poorer scores across all PROMs. Conclusion Patients with musculoskeletal symptoms who are at risk of RA present with a high health burden. Early intervention may be needed to improve quality of life from initial presentation. Disclosure B. Torlinska: Corporate appointments; BT is employed by Visible Analytics Ltd.. Grants/research support; BT receives funding from the NIHR. K. Raza: Consultancies; KR declares personal fees from Abbvie and Sanofi outside of the submitted work. Grants/research support; KR declares funding from Bristol Myers Squibb outside of the submitted work, KR is supported by the NIHR Birmingham Biomedical Research Centre, the MRC Versus Arthritis Centre for Musculoskeletal Ageing Research and the Research into Inflammatory Arthritis Centre Versus Arthritis, University of Birmingham, UK. A. Filer: Grants/research support; AF is supported by the NIHR Birmingham Biomedical Research Centre, the MRC Versus Arthritis Centre for Musculoskeletal Ageing Research and the Research into Inflammatory Arthritis Centre Versus Arthritis, University of Birmingham, UK, AF declares funding outside of the submitted work from Abbvie, Roche, Janssen, UCB, Nascient, Mestag, GSK. G. Jutley: None. I. Sahbudin: None. R. Singh: None. P. de Pablo: None. E. Rankin: None. B. Rhodes: None. N. Amft: None. E. Justice: None. C. McGrath: None. S. Baskar: None. J. Trickey: None. M. Calvert: Consultancies; MC has received personal fees outside of the submitted work from Astellas, Aparito Ltd., CIS Oncology, Takeda, Merck, Daiichi Sanko, Glaukos, GSK, and the Patient-Centered Outcomes Research Institute. Grants/research support; MC is Director of the Birmingham Health Partners Centre for Regulatory Science and Innovation, Director of the Centre for Patient Reported Outcomes Research and is a NIHR Senior Investigator, MC receives funding from NIHR, UKRI, NIHR Birmingham Biomedical Research Centre, NIHR Surgical Reconstruction and Microbiology Research Centre, NIHR ARC West Midlands, UK Spine and Health Data Research at the University of Birmingham and University Hospitals Birmingham, UK, Innovate UK (part of UK Research and InnovatioRin), Macmillan Cancer Support, UCB Pharma, Janssen, GSK, and Gilead. M. Falahee: None.

The Role of Genetics in Clinically Suspect Arthralgia and Rheumatoid Arthritis Development: A Large Cross-Sectional Study.

To investigate whether established genetic predictors for rheumatoid arthritis (RA) differentiate healthy controls, patients with clinically suspect arthralgia (CSA), and RA patients. Using analyses of variance, chi-square tests, and mean risk difference analyses, we investigated the association of an RA polygenic risk score (PRS) and HLA shared epitope (HLA-SE) with all participant groups, both unstratified and stratified for anti-citrullinated protein antibody (ACPA) status. We used 3 separate data sets sampled from the same Dutch population (1,015 healthy controls, 479 CSA patients, and 1,146 early classified RA patients). CSA patients were assessed for conversion to inflammatory arthritis over a period of 2 years, after which they were classified as either CSA converters (n=84) or CSA nonconverters (n=395). The PRS was increased in RA patients (mean ± SD PRS 1.31 ± 0.96) compared to the complete CSA group (1.07 ± 0.94) and compared to CSA converters (1.12 ± 0.94). In ACPA- strata, PRS distributions differed strongly when comparing the complete CSA group (mean ± SD PRS 1.05 ± 0.94) and CSA converters (0.97 ± 0.87) to RA patients (1.20 ± 0.94), while in the ACPA+ strata, the complete CSA group (1.25 ± 0.99) differed clearly from healthy controls (1.05 ± 0.94) and RA patients (1.41 ± 0.96). HLA-SE was more prevalent in the RA group (prevalence 0.64) than the complete CSA group (0.45), with small differences between RA patients and CSA converters (0.64 versus 0.60) and larger differences between CSA converters and CSA nonconverters (0.60 versus 0.42). HLA-SE prevalence differed more strongly within the ACPA+ strata as follows: healthy controls (prevalence 0.43), CSA nonconverters (0.48), complete CSA group (0.59), CSA converters (0.66), and RA patients (0.79). We observed that genetic predisposition increased across pre-RA participant groups. The RA PRS differed in early classified RA and inflammatory pre-disease stages, regardless of ACPA stratification. HLA-SE prevalence differed between arthritis patients, particularly ACPA+ patients, and healthy controls. Genetics seem to fulfill different etiologic roles.

The course of fatigue during the development of rheumatoid arthritis and its relation with inflammation: a longitudinal study.

Fatigue is a prominent and disabling symptom in patients with rheumatoid arthritis (RA), that is only partially explained by inflammation and responds poorly to DMARD-therapy. We hypothesized that inflammation explains fatigue to a larger extent in the phase of clinically suspect arthralgia (CSA), when persistent clinical arthritis is still absent and fatigue has not yet become chronic. We therefore studied the course of fatigue in CSA during progression to RA and the association with inflammation at CSA-onset and at RA-diagnosis. 600 consecutive CSA-patients were followed for RA-development. Additionally, 710 early RA-patients were studied at diagnosis. Fatigue was assessed every study visit and expressed on a 0-100 scale. Inflammation was measured with the DAS44-CRP, with and without including subclinical inflammation. The course of fatigue over time was studied with linear mixed models. Associations between fatigue and inflammation were studied with linear regression. Analyses were stratified by ACPA-status. In 88 CSA-patients who developed RA, pre-arthritis fatigue-levels increased gradually with 7 points/year, towards 48 (95%CI=41-55) at RA-development (P=ns). Fatigue decreased in CSA-patients who did not develop RA (4 points/year, P<0.001). At CSA-onset, inflammation was associated with fatigue (β=18, meaning 18 points more fatigue per point increase DAS-score, P<0.01). This association was stronger than at RA-diagnosis (β=5, P<0.001). Fatigue-levels were lower in ACPA-positive pre-RA, but its association with inflammation was stronger compared to ACPA-negative pre-RA. Fatigue increased gradually during progression from arthralgia to clinical arthritis, and fatigue was better explained by inflammation in CSA than in RA. This implies a 'phase-dependent relation' between inflammation and fatigue.

Anti-Citrullinated Peptide Antibodies Control Oral Porphyromonas and Aggregatibacter species in Patients with Rheumatoid Arthritis.

Oral microbiome changes take place at the initiation of rheumatoid arthritis (RA); however, questions remain regarding the oral microbiome at pre-RA stages in individuals with clinically suspect arthralgia (CSA). Two cross-sectional cohorts were selected including 84 Tatarstan women (15 early-RA as compared to individuals with CSA ranging from CSA = 0 [n = 22], CSA = 1 [n = 19], CSA = 2 [n = 11], and CSA ≥ 3 [n = 17]) and 42 women with established RA (median: 5 years from diagnosis [IQ: 2–11]). Amplicon sequence variants (ASVs) obtained from oral samples (16S rRNA) were analyzed for alpha and beta diversity along with the abundance at the genus level. A decrease in oral Porphyromonas sp. is observed in ACPA-positive individuals, and this predominates in early-RA patients as compared to non-RA individuals irrespective of their CSA score. In the RA-established cohort, Porphyromonas sp. and Aggregatibacter sp. reductions were associated with elevated ACPA levels. In contrast, no associations were reported when considering individual, genetic and clinical RA-associated factors. Oral microbiome changes related to the genera implicated in post-translational citrullination (Porphyromonas sp. and Aggregatibacter sp.) characterized RA patients with elevated ACPA levels, which supports that the role of ACPA in controlling the oral microbiome needs further evaluation.

Clinically suspect arthralgia patients with a low educational attainment have an increased risk of developing inflammatory arthritis.

Cross-sectional studies have shown that rheumatoid arthritis is more prevalent among people with a lower educational attainment. No longitudinal data are present on educational attainment in the at-risk phase of clinically suspect arthralgia (CSA). We therefore analysed the association between educational attainment and progression from CSA to inflammatory arthritis (IA), and performed mediation analysis with subclinical joint inflammation to elucidate pathways of this association. A total of 521 consecutive patients presenting with CSA were followed for IA development during median 25 months. Educational attainment was defined as low (lower secondary vocational education), intermediate or high (college/university education). Subclinical inflammation in hand and foot joints was measured at presentation with contrast enhanced 1.5 T-MRI. Cox-regression was used to analyse IA development per educational attainment. A three-step mediation analysis evaluated whether subclinical joint inflammation was intermediary in the path between educational attainment and IA development, before and after age correction. Association between educational attainment and IA development was verified in an independent CSA cohort. Low educational attainment was associated with increased IA development (HR = 2.35, 95% CI = 1.27, 4.33, P = 0.006), independent of BMI and current smoking status (yes/no). Moreover, patients with a low educational attainment had higher levels of subclinical inflammation, which also was associated with IA development. Partial mediation effect of subclinical inflammation was observed in the relationship between education and IA development. Low educational attainment was also associated with increased IA development in the validation cohort (HR = 5.72, 95% CI = 1.36, 24.08, P = 0.017). This is the first study providing evidence that lower educational attainment is associated with a higher risk of progressing from arthralgia to IA. This effect was partially mediated by subclinical joint inflammation.

Ultrasound in clinically suspect arthralgia: the role of power Doppler to predict rheumatoid arthritis development

ObjectiveTo determine the usefulness of power Doppler (PD) ultrasound (US) to predict rheumatoid arthritis (RA) development in patients with clinically suspect arthralgia (CSA).MethodsRetrospective analysis of a US unit cohort over a 1-year period. Patients with CSA and no previous diagnosis of inflammatory arthritis (IA) were included for analysis. All underwent bilateral US examination of the hands and/or feet according to the EULAR guidelines. Active US inflammation was defined as PD synovitis and/or tenosynovitis ≥1 at any location. RA diagnosis according to clinician criteria 6 months after the US examination was checked. Univariate and multivariate logistic regression models were employed to investigate possible predictive factors of RA development.ResultsA total of 110 CSA patients (80 females, mean age 53.6 years) were included for analysis. After 6 months of follow-up, 14 (12.7%) developed RA and 34 (30.9%) IA. US active inflammation was present in 38 (34.5%) patients (28.2% showed PD synovitis and 18.2% PD tenosynovitis). Multivariate analysis showed that ACPA (OR 1.0003; 95% CI 1.002–1.006) and ESR (OR 1.054; 95% CI 1.016–1.094) were significantly associated with the detection of US active inflammation at baseline. Only PD tenosynovitis was found to be an independent predictive factor of an evolution towards RA (OR 6.982; 95% CI 1.106–44.057) and IA (OR 5.360; 95% CI 1.012–28.390).ConclusionUS is able to detect features of subclinical inflammation in CSA patients, especially in those with higher ESR and ACPA values. Only PD tenosynovitis at baseline US assessment was found to be an independent predictor of RA and IA development in CSA patients.

During development of rheumatoid arthritis, intermetatarsal bursitis may occur before clinical joint swelling: a large imaging study in patients with clinically suspect arthralgia.

ObjectivesIntermetatarsal bursitis (IMB) represents juxta-articular synovial inflammation of the intermetatarsal bursae. Recent MRI studies identified IMB as feature of early RA, but whether IMB already occurs in the pre-arthritic phase is unknown. We performed a large MRI study in clinically suspect arthralgia (CSA) to assess the occurrence and prognostic value of IMB.MethodsA total of 577 consecutive CSA patients underwent contrast-enhanced MRI of the forefoot, metacarpophalangeal joints and wrist. MRIs were evaluated for subclinical synovitis/tenosynovitis/osteitis in line with the RA MRI scoring system (summed as RAMRIS inflammation) and for IMB. IMB was considered present if uncommon in the general population at the same location (i.e. size scored above the 95th percentile in age-matched symptom-free controls). The relation of IMB with other MRI-detected subclinical inflammation (synovitis/tenosynovitis/osteitis) was studied. Cox-regression assessed the association with clinical arthritis development during median 25 months follow-up. ACPA stratification was performed.ResultsAt presentation with CSA, 23% had IMB. IMB was more frequent in ACPA-positive than ACPA-negative CSA (47% vs 19%, P < 0.001). Patients with IMB were more likely to also have subclinical synovitis [OR 3.4 (95% CI 1.8, 6.5)] and tenosynovitis [5.9(2.8, 12.6)]. IMB conferred higher risk of developing arthritis [HR 1.6(1.0–2.7) adjusted for other subclinical inflammation]. IMB-presence predicted arthritis development in ACPA-positive CSA [adjusted HR 2.2(1.0–4.7)], but not in ACPA-negative CSA-patients [0.8(0.4–1.7)].ConclusionApproximately a quarter of CSA patients have IMB, which is frequently accompanied by subclinical synovitis and tenosynovitis. IMB precedes development of clinical arthritis, particularly in ACPA-positive CSA. These results reinforce the notion that juxta-articular synovial inflammation is involved in the earliest phases of RA development.

Clinically suspect arthralgia – are we going towards a new shift in the therapeutic paradigm of rheumatoid arthritis?

Background. There is a time sensitive window of opportunity in rheumatoid arthritis (RA) in which therapeutic intervention is more effective, the disease being more susceptible to the immunomodulatory effects of the remissive medication. The goal is to prevent osteo-articular damage, which causes severe functional deficit, and to raise the chance to lead the disease in remission. Evolution towards RA represents a multi-step process. In other medical fields prevention has the same important role as treatment, so could we in the future switch again the therapeutic paradigm in RA, from early treatment to prevention of RA, by treating patients with high risk of developing disease? Initiating treatment in the pre-RA phases could potentially lead to a better immune modulation or even preventing disease development by acting on less mature pathogenic processes. Treating in the initial symptomatic phase of the disease could potentially be more effective in reducing disease persistence and the development of structural lesions. The clinically suspect arthralgia (CSA) definition offers a support of clinical parameters for future longitudinal studies, where together with para clinical parameters, laboratory studies and imagistic studies, could lead to the development of imminent RA classification criteria. Currently there are more ongoing studies that have the primary objective to prove this concept with different subpopulations and treatments, but most of them have inclusion criteria based on the presence of autoantibodies. The publication of this trials results in the next decade will help to better understand the efficacy of therapeutic intervention with the scope of preventing chronic arthritis and what subset of patients at risk to treat. There are no recommendations for management of CSA, but current practice is symptomatic treatment with nonsteroidal anti-inflammatory drugs, pain relievers and of course monitoring.

Morning stiffness precedes the development of rheumatoid arthritis and associates with systemic and subclinical joint inflammation in arthralgia patients.

ObjectivesMorning stiffness (MS) is characteristic of RA and associates with markers of systemic and local inflammation in RA patients. In patients with arthralgia, MS is a cardinal symptom to recognize arthralgia at-risk for RA development [i.e. clinically suspect arthralgia (CSA)]. In CSA, MS is also assumed to reflect inflammation, but this has never been studied. Therefore we aimed to study whether MS in CSA patients is associated with systemic and subclinical joint inflammation.MethodsA total of 575 patients presenting with CSA underwent laboratory investigations and contrast-enhanced 1.5 T MRI of the hand and forefoot (scored according to the Rheumatoid Arthritis MRI Score method). Associations of MS (duration ≥60 min) with the presence of subclinical joint inflammation (synovitis, tenosynovitis and osteitis) and increased CRP (≥5 mg/l) were determined with logistic regression. Additionally, the effect of MS duration (≥30, ≥60 and ≥120 min) was studied.ResultsA total of 195 (34%) CSA patients experienced MS. These patients more often had subclinical synovitis [34% vs 21%; odds ratio (OR) 1.95 (95% CI 1.32, 2.87)], subclinical tenosynovitis [36% vs 26%; OR 1.59 (95% CI 1.10, 2.31)] and increased CRP [31% vs 19%; OR 1.93 (95% CI 1.30, 2.88)] than patients without MS. In multivariable analyses, subclinical synovitis [OR 1.77 (95% CI 1.16, 2.69)] and CRP [OR 1.78 (95% CI 1.17–2.69)] remained independently associated with MS. In CSA patients who later developed RA, and thus in retrospect were ‘pre-RA’ at the time of CSA, MS was more strongly associated with subclinical synovitis [OR 2.56 (95% CI 1.04, 6.52)] and CRP [OR 3.86 (95% CI 1.45, 10.24)]. Furthermore, associations increased with longer MS durations.ConclusionInflammation associates with MS in the CSA phase that preceded clinical arthritis. These results increase our understanding of MS when assessing arthralgia in clinical practice.

Determining in which pre-arthritis stage HLA-shared epitope alleles and smoking exert their effect on the development of rheumatoid arthritis

ObjectivesThe human leukocyte antigen-shared epitope (HLA-SE) alleles and smoking are the most prominent genetic and environmental risk factors for rheumatoid arthritis (RA). However, at which pre-arthritis stage (asymptomatic/symptomatic) they exert...

POS0379 DETERMINING IN WHICH PRECLINICAL STAGE HLA-SHARED EPITOPE ALLELES AND SMOKING EXERT THEIR EFFECT IN THE DEVELOPMENT OF RHEUMATOID ARTHRITIS

Background:The HLA shared epitope (SE) and smoking are the best known genetic and environmental risk factors for rheumatoid arthritis (RA) development; however, at which pre-RA stage they exert their effect is unknown. The following stages are discerned: an asymptomatic stage in which autoimmune responses can develop, a symptomatic stage (clinically suspect arthralgia (CSA)), and development of clinically apparent inflammatory arthritis (IA). Studies in the general asymptomatic population revealed contrasting results on the associations between SE-alleles and smoking and the presence of anti-citrullinated protein antibodies (ACPA). Furthermore, studies on these risk factors in the symptomatic pre-RA phase are scarce and these data might teach us whether SE-alleles and smoking are involved in symptom development and/or progression to clinical arthritis.Objectives:We aimed to determine at which pre-RA stage SE and smoking exert their effect. In this respect, the analyses were focused on the presence of ACPA, but associations for other anti-modified protein antibodies (anti-carbamylated and anti-acetylated protein antibodies (anti-CarP and AAPA, respectively)) were also studied.Methods:Results from the literature on the association of SE and smoking with ACPA in the asymptomatic population were summarized in inverse-variance weighted meta-analyses. In addition 577 CSA-patients were studied. Associations of SE and smoking with IgG ACPA were studied at baseline (CSA-onset), to assess an effect on symptom development. Additionally, patients were monitored for the development of clinically apparent inflammatory arthritis (IA) for median 2 years and associations of SE, smoking and auto-antibodies with progression to IA were determined. Analyses were stratified for ACPA-status and associations in ACPA-positive patients were validated in meta-analyses with other arthralgia-cohorts. Finally analyses were repeated for anti-CarP and AAPA.Results:Meta-analyses showed that SE is not associated with ACPA-positivity in the asymptomatic population (OR 1.06 (95%CI 0.69-1.64)), whereas smoking was associated (OR 1.37 (1.15-1.63)). At CSA-onset, both SE and smoking associated with ACPA-positivity (OR 2.08 (1.24-3.49) and OR 2.41 (1.31-4.43), respectively). During follow-up of CSA-patients SE associated with IA-development (HR 1.86 (1.23-2.82)), in contrast to smoking. SE conferred risk for IA-development in ACPA-negative CSA-patients (HR 1.71 (0.99-2.96)) and in ACPA-positive patients (CSA-cohort HR 1.29 (0.67-2.47); meta-analysis three arthralgia-cohorts HR 1.52 (1.08-2.15)). Investigating the other autoantibodies revealed that SE and smoking were not associated with anti-CarP or AAPA-positivity at CSA-onset; longitudinally AAPA associated with progression to IA independent from ACPA and RF (HR 1.79 (1.02-3.16)), whilst anti-Carp did not.Conclusion:SE and smoking act in partly different pre-RA stages. Although SE does not associate with ACPA in the general population, it does mediate symptom-development and further progression to clinical arthritis. Smoking confers risk to development of ACPA and/or joint symptoms, but is not further involved in IA-development. The time-specific biologic pathways that are underlying need further exploration. These data enhance the understanding of the timing of key genetic and environmental risk factors in the trajectory of RA development.Disclosure of Interests:None declared

Profiling of Serum Oxylipins During the Earliest Stages of Rheumatoid Arthritis.

Eicosanoids modulate inflammation via complex networks involving different pathways and downstream mediators, including oxylipins. Although altered eicosanoids are linked to rheumatoid arthritis (RA), suggesting that metabolization is enhanced, the role of oxylipins in disease stratification remains unexplored. This study was undertaken to characterize oxylipin networks during the earliest stages of RA and evaluate their associations with clinical features and treatment outcomes. In total, 60 patients with early RA (according to the American College of Rheumatology/European League Against Rheumatism 2010 criteria), 11 individuals with clinically suspect arthralgia (CSA), and 28 healthy control subjects were recruited. Serum samples were collected at the time of onset. In the early RA group, 50 patients who had not been exposed to disease-modifying antirheumatic drug (DMARD) or glucocorticoid treatment at the time of recruitment were prospectively followed up at 6 and 12 months after having received conventional synthetic DMARDs. A total of 75 oxylipins, mostly derived from arachidonic, eicosapentanoic, and linoleic acids, were identified in the serum by liquid chromatography tandem mass spectrometry. Univariate analyses demonstrated differences in expression patterns of 14 oxylipins across the RA, CSA, and healthy control groups, with each exhibiting a different trajectory. Network analyses revealed a strong grouping pattern of oxylipins in RA patients, whereas in individuals with CSA, a fuzzy network of oxylipins with higher degree and closeness was found. Partial least-squares discriminant analyses yielded variable important projection scores of >1 for 22 oxylipins, which allowed the identification of 2 clusters. Cluster usage differed among the groups (P = 0.003), and showed associations with disease severity and low rates of remission at 6 and 12 months in RA patients who were initially treatment-naive. Pathway enrichment analyses revealed different precursors and pathways between the groups, highlighting the relevance of the arachidonic acid pathway in individuals with CSA and the lipooxygenase pathway in patients with early RA. In applying distinct oxylipin signatures, subsets of seropositive and seronegative RA could be identified. Oxylipin networks differ across stages during the earliest phases of RA. These distinct oxylipin networks could potentially elucidate pathways with clinical relevance for disease progression, clinical heterogeneity, and treatment response.