The prognostic value of IgA anti-citrullinated protein antibodies and rheumatoid factor in an early arthritis population with a treat-to-target approach.

The mucosal origin hypothesis of rheumatoid arthritis has renewed the interest in IgA autoantibodies, but their added value over IgG anti-citrullinated protein antibody (ACPA) and IgM rheumatoid factor (RF) for modern treatment outcomes remains unknown. We aimed to investigate the prognostic value of IgA-ACPA and IgA-RF for treatment outcomes in an early arthritis population. IgA-ACPA/RF isotypes were measured in baseline sera from 480 inflammatory arthritis (IA) patients, who were included in the treatment in the Rotterdam Early Arthritis Cohort trial (tREACH). The tREACH trial was a multicentre, stratified, single-blinded trial with a treat-to-target approach. The prognostic value of IgA-ACPA/RF was determined by evaluating differences in (1) quick-attained (< 6 months after diagnosis) and persistent remission rates, (2) DMARD-free remission and (3) biological use between IA patients with and without IgA-ACPA/RF over 3 years of follow-up. IgA-ACPA was present in 23% of patients and overlapped with IgG-ACPA positivity in 94%. Similarly, IgA-RF overlapped with IgM-RF in 90% of patients. IgA-ACPA positivity was associated with lower DFR rates and more biological use, but this effect was largely mediated by the presence of IgG-ACPA, since this effect disappeared after stratification for IgG-ACPA (HR 0.6, 95%CI 0.2-1.6 for DFR). No differences were observed in 'quick-attained and persistent remission' rates and for IgA-RF. Their seems to be no additional value of IgA-ACPA and IgA-RF for modern, long-term clinical outcomes. The effects of IgA-ACPA seen in our study are largely mediated by the presence of IgG-ACPA. Based on these results, there is no rationale for measuring these isotypes in daily practice.

Clinically suspect arthralgia and rheumatoid arthritis: patients' perceptions of illness.

OBJECTIVES: Clinically suspect arthralgia (CSA) is an at-risk stage of rheumatoid arthritis (RA), in which patients experience symptoms and physical limitations. Perceptions of CSA-patients have remained largely unknown. Therefore, we aimed to map perceptions of CSA-patients and compare these to RA-patients. Additionally, we studied changes in perceptions in CSA over time. METHODS: Three hundred and ninety-nine consecutively included CSA-patients from the Leiden and Rotterdam CSA-cohorts and 100 recently diagnosed RA-patients from the Leiden Early Arthritis Clinic were included. Patients' illness perceptions (IP) were assessed using the Brief Illness Perception Questionnaire (BIPQ), consisting of 8 questions (scale 0-10; higher score indicating more negative IP) covering cognitive, emotional and comprehensibility domains, and one open question about causes of disease. IP were measured at baseline in both populations and during 2years follow-up in the CSA-cohorts. RESULTS: Total BIPQ-scores were comparable at CSA-presentation and RA-diagnosis (40±11 and 40±10; range 0-80). Comparing dimensions separately revealed that CSA-patients were less worried about physical complaints compared to RA-patients. However, CSA-patients were more negative about expected treatment-effect on symptoms. IP over time in CSA improved in patients without development of clinical arthritis (from 38±11 to 34±14; P=0.005) but remained similar in CSA-patients who progressed to arthritis/RA (mean 40 at both timepoints). CSA-patients mainly perceived physical strain and heredity as causes of their complaints. CONCLUSIONS: Although CSA-patients have not developed clinical arthritis, illness perceptions at CSA-presentation and RA-diagnosis are equally severe. Knowledge on worries and expectations may contribute to improving patient-contact and care in patients at risk of RA.

RPA3-UMAD1 rs12702634 and rheumatoid arthritis-associated interstitial lung disease in European ancestry.

Objective: Recently, a genome-wide association study identified an association between RA-associated interstitial lung disease (ILD) and RPA3-UMAD1 rs12702634 in the Japanese population, especially for patients with a usual interstitial pneumonia (UIP) pattern. We aimed to replicate this association in a European population and test for interaction with MUC5B rs35705950. Methods: In this genetic case-control association study, patients with RA and ILD and controls with RA and no ILD were included from France, the USA and the Netherlands. Only cases and controls from European genetic ancestries determined by principal components analysis were included in the analyses. RA was defined by the 1987 ACR or 2010 ACR/EULAR criteria and ILD by chest high-resolution CT scan, except in the control dataset from the Netherlands, where the absence of ILD was determined by chart review. Patients were genotyped for RPA3-UMAD1 rs12702634 and MUC5B rs35705950. Associations were tested using logistic regression adjusted for sex, age at RA onset, age at ILD onset or at certified absence of ILD, tobacco smoking status and country of origin. Results: Among the 883 patients included, 322 were RA-ILD cases (36.5%). MUC5B rs35705950 was strongly associated with RA-ILD in all datasets {combined adjusted odds ratio [OR] 2.9 [95% CI 2.1, 3.9], P = 1.1 × 10-11. No association between RPA3-UMAD1 rs12702634 and RA-ILD was observed [combined OR 1.2 (95% CI 0.8, 1.6), P = 0.31. No interaction was found between RPA3-UMAD1 rs12702634 and MUC5B rs35705950 (P = 0.70). Conclusion: Our findings did not support a contribution of RPA3-UMAD1 rs12702634 to the overall RA-ILD susceptibility in the European population.

Ultrasound of the forefeet besides the hands in patients at risk for rheumatoid arthritis: is it worth the effort? A longitudinal cohort study.

OBJECTIVE: Ultrasound (US) can detect subclinical joint-inflammation in patients with clinically suspect arthralgia (CSA), which is valuable as predictor for rheumatoid arthritis (RA) development. In most research protocols both hands and forefeet are scanned, but it is unclear if US of the forefeet has additional value for predicting RA, especially since synovial hypertrophy in MTP-joints of healthy individuals is also common. To explore the possibility to omit scanning of the forefeet we determined if US of the forefeet is of additional predictive value for RA-development in CSA patients. METHODS: CSA patients of two independent cohorts underwent US of the hands and forefeet. We analyzed the association between RA-development and US-positivity for the full US-protocol, the full US-protocol with correction for Gray Scale(GS)-findings in the forefeet of healthy and the protocol without-forefeet. RESULTS: In total, 298 CSA patients were studied. In patients with a positive US, subclinical joint-inflammation was mostly present in the hands (90-86%). Only 10-14% of patients had subclinical joint-inflammation solely in the forefeet. US-positivity was associated with inflammatory arthritis development in both cohorts, with HRs 2.6(95%CI 0.9-7.5) and 3.1(95%CI 1.5-6.4) for the full protocol, 3.1(95%CI 1.3-7.7) and 2.7(95%CI 1.3-5.4) for the full US-protocol with correction, and 3.1(95%CI 1.4-6.9) and 2.8(95%CI 1.4-5.6) without the forefeet. AUROCs were equal across both cohorts. CONCLUSION: The forefeet can be omitted when US is used for the prediction of RA-development in CSA patients. This is due to the finding that subclinical joint-inflammation in the forefeet without concomitant inflammation in the hands is infrequent.

Responsiveness and sensitivity of PROMs to change in disease activity status in early and established rheumatoid arthritis.

OBJECTIVES: To determine whether patient reported outcome measures (PROMs) capturing activity limitations, health impact, pain, fatigue and work ability are responsive and sensitive to changes in disease activity status in patients with early and established rheumatoid arthritis (RA). METHODS: All early RA patients (n = 557) from the tREACH-trial and established RA patients (n = 188) from the TARA-trial were included. Both studies were multicentre, single-blinded trials with a treat-to-target management approach. The following PROMs were studied: Health Assessment Questionnaire Disability Index(HAQ-DI), morning stiffness severity, EQ-5D, general health, 36-item short form(SF-36), joint pain, fatigue and productivity loss. Mean changes in PROMs between two consecutive visits were compared with changes in disease activity status(remission, low disease activity and active disease) using linear mixed models and standardised response means. Additionally, the proportion of individual observations that showed an expected PROM response to disease activity status alterations was calculated. RESULTS: HAQ-DI, morning stiffness severity, general health, EQ-5D and joint pain demonstrated responsiveness to improvement or worsening of disease activity status in both early and established RA. SF-36 physical and mental component scale, fatigue and productivity loss did not show this effect in both groups. Across nearly all PROMs, the magnitude of change and the proportion of individual observations that reflect a shift from and to active disease remained low. CONCLUSION: HAQ-DI, morning stiffness severity, EQ-5D, general health and joint pain are responsive to disease activity status alterations on a group level in both early and established RA. For the individual patient the responsiveness of these PROMs is poor. CLINICAL TRIAL REGISTRATION: tREACH trial (www.isrctn.com, ISRCTN26791028) and TARA trial (www.onderzoekmetmensen.nl, NTR2754).

Work-related physical strain and development of joint inflammation in the trajectory of emerging inflammatory and rheumatoid arthritis: a prospective cohort study.

OBJECTIVES: Rheumatoid arthritis (RA) mainly affects small joints. Despite the mechanical function of joints, the role of mechanical stress in the development of arthritis is insufficiently understood. We hypothesised that mechanical stress/physical strain is a risk factor for joint inflammation in RA. Therefore, we studied work-related physical strain in subjects with clinically suspected arthralgia (CSA) as a risk factor for the presence of imaging-detected subclinical joint inflammation and the development of clinical arthritis/RA. METHODS: In 501 CSA patients and 155 symptom-free persons' occupation-related physical strain was quantified using the International Standard Classification of Occupations. Contrast-enhanced hand-MRIs were made and evaluated for joint inflammation (sum of synovitis/tenosynovitis/osteitis). CSA patients were followed on RA development. Age relationship was studied using an interaction term of physical strain with age. RESULTS: The degree of physical strain in CSA is associated with the severity of joint inflammation, independent of educational-level/BMI/smoking (interaction physical strain-age p=0.007; indicating a stronger association with increasing age). Physical strain is associated with higher tenosynovitis scores, in particular. In symptom-free persons, physical strain was not associated with imaging-detected joint inflammation. Higher degrees of physical strain also associated with higher risks for RA development in an age-dependent manner (HR=1.20 (1.06-1.37)/10-year increase in age), independent of educational-level/BMI/smoking. This association was partly mediated by an effect via subclinical joint inflammation. CONCLUSIONS: Work-related physical strain increases the risk of subclinical joint inflammation and of developing RA. The age relationship suggests an effect of long-term stress or that tenosynovium is more sensitive to stress at older age. Together, the data indicate that mechanical stress contributes to the development of arthritis in RA.

EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2023 update.

OBJECTIVE: New modes of action and more data on the efficacy and safety of existing drugs in psoriatic arthritis (PsA) required an update of the EULAR 2019 recommendations for the pharmacological treatment of PsA. METHODS: Following EULAR standardised operating procedures, the process included a systematic literature review and a consensus meeting of 36 international experts in April 2023. Levels of evidence and grades of recommendations were determined. RESULTS: The updated recommendations comprise 7 overarching principles and 11 recommendations, and provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs should be used in monotherapy only for mild PsA and in the short term; oral glucocorticoids are not recommended. In patients with peripheral arthritis, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended and methotrexate preferred. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drug (bDMARD) should be initiated, without preference among modes of action. Relevant skin psoriasis should orient towards bDMARDs targeting interleukin (IL)-23p40, IL-23p19, IL-17A and IL-17A/F inhibitors. In case of predominant axial or entheseal disease, an algorithm is also proposed. Use of Janus kinase inhibitors is proposed primarily after bDMARD failure, taking relevant risk factors into account, or in case bDMARDs are not an appropriate choice. Inflammatory bowel disease and uveitis, if present, should influence drug choices, with monoclonal tumour necrosis factor inhibitors proposed. Drug switches and tapering in sustained remission are also addressed. CONCLUSION: These updated recommendations integrate all currently available drugs in a practical and progressive approach, which will be helpful in the pharmacological management of PsA.

Patient-reported outcomes and radiographic progression in patients with rheumatoid arthritis in sustained remission versus low disease activity.

OBJECTIVE: To compare clinical and patient-reported outcomes (PROs) over 5 years between patients with rheumatoid arthritis (RA) in sustained remission (sREM), sustained low disease activity (sLDA) or active disease (AD) in the first year after diagnosis. METHODS: All patients with RA from the treatment in the Rotterdam Early Arthritis CoHort trial, a multicentre, stratified, single-blinded trial with a treat-to-target approach, aiming for LDA (Disease Activity Score (DAS) ≤2.4), were studied. Patients were categorised into: (1) sREM (mean DAS from 6 to 12 months <1.6) (n=173); (2) sLDA (mean DAS from 6 to 12 months 1.6-2.4) (n=142); and (3) AD (mean DAS from 6 to 12 months >2.4) (n=59). Pain, fatigue, functional impairment, health-related quality of life (HRQoL), health status and productivity loss during 5 years were compared between groups. Radiographic progression (modified Total Sharp Score (mTSS)) was compared over 2 years. RESULTS: Patients in sLDA in the first year had worse PROs during follow-up, compared with patients in sREM: pain (0-10 Likert) was 0.90 units higher (95% CI 0.52 to 1.27), fatigue (Visual Analogue Scale) was 12.10 units higher (95% CI 7.27 to 16.92), functional impairment (Health Assessment Questionnaire-Disability Index) was 0.28 units higher (95% CI 0.17 to 0.39), physical HRQoL (36-item Short Form Health Survey (SF-36) Physical Component Summary score) was 4.42 units lower (95% CI -6.39 to -2.45), mental HRQoL (SF-36 Mental Component Summary score (MCS)) was 2.95 units lower (95% CI -4.83 to -1.07), health status (European Quality of life 5-Dimensions 3-Levels (EQ-5D-3L)) was 0.06 units lower (95% CI -0.09 to -0.03) and productivity loss (0%-100%) was 7.76% higher (95% CI 2.76 to 12.75). Differences between the AD and sREM group were even larger, except for the SF-36 MCS and EQ-5D-3L. No differences in mTSS were found between groups. CONCLUSION: Patients with RA who reach sREM in the first year have better HRQoL and function, and less pain, fatigue and productivity loss in the years thereafter, compared with patients with RA who are in sLDA or AD in the first year.

Window of opportunity in psoriatic arthritis: the earlier the better?

OBJECTIVES: To investigate whether there is a window of opportunity for psoriatic arthritis (PsA) patients and to assess which patient characteristics are associated with a longer diagnostic delay. METHODS: All newly diagnosed, disease-modifying antirheumatic drug-naïve PsA patients who participated in the Dutch southwest Early PsA cohoRt and had ≥3 years of follow-up were studied. First, total delay was calculated as the time period between symptom onset and PsA diagnosis made by a rheumatologist and then split into patient and physician delays. The total delay was categorised into short (<12 weeks), intermediate (12 weeks to 1 year) or long (>1 year). These groups were compared on clinical (Minimal Disease Activity (MDA) and Disease Activity index for PSoriatic Arthritis (DAPSA) remission) and patient-reported outcomes during 3 years follow-up. RESULTS: 708 PsA patients were studied of whom 136 (19%), 237 (33%) and 335 (47%) had a short, intermediate and long total delay, respectively. Patient delay was 1.0 month and physician delay was 4.5 months. Patients with a short delay were more likely to achieve MDA (OR 2.55, p=0.003) and DAPSA remission (OR 2.35,p=0.004) compared with PsA patients with a long delay. Patient-reported outcomes showed numerical but non-significant differences between the short and long delay groups. Female patients and those presenting with enthesitis, chronic back pain or normal C-reactive protein (CRP) had a longer delay. CONCLUSIONS: In PsA, referral and diagnosis within 1 year is associated with better clinical outcomes, suggesting the presence of a window of opportunity. The most gain in referral could be obtained in physician delay and in females, patients with enthesitis, chronic back pain or normal CRP.

Deep learning in rheumatological image interpretation.

Artificial intelligence techniques, specifically deep learning, have already affected daily life in a wide range of areas. Likewise, initial applications have been explored in rheumatology. Deep learning might not easily surpass the accuracy of classic techniques when performing classification or regression on low-dimensional numerical data. With images as input, however, deep learning has become so successful that it has already outperformed the majority of conventional image-processing techniques developed during the past 50 years. As with any new imaging technology, rheumatologists and radiologists need to consider adapting their arsenal of diagnostic, prognostic and monitoring tools, and even their clinical role and collaborations. This adaptation requires a basic understanding of the technical background of deep learning, to efficiently utilize its benefits but also to recognize its drawbacks and pitfalls, as blindly relying on deep learning might be at odds with its capabilities. To facilitate such an understanding, it is necessary to provide an overview of deep-learning techniques for automatic image analysis in detecting, quantifying, predicting and monitoring rheumatic diseases, and of currently published deep-learning applications in radiological imaging for rheumatology, with critical assessment of possible limitations, errors and confounders, and conceivable consequences for rheumatologists and radiologists in clinical practice.

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

OBJECTIVES: Obesity 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 (CSA) phase of risk. To improve understanding of the effect of obesity on RA development, we aimed to (1) compare body mass index (BMI) at CSA onset to BMI of the general population and (2) study within CSA patients if obesity increases the risk for progression to RA. METHODS: 1107 symptomatic persons at risk for RA from four cohorts (CSA Leiden, CSA Rotterdam, SONAR and TREAT EARLIER placebo arm) were studied. For the first aim, baseline BMI was compared with age-matched/sex-matched BMI of the general population. Patients were stratified for anticitrullinated protein antibody (ACPA) status. Regarding the second aim, the association between BMI and inflammatory arthritis (IA) development during 2 years was studied with Cox regression analysis within each cohort and via meta-analysis in all cohorts. RESULTS: CSA patients of all cohorts were more often obese than the general population (respectively 21.9% vs 14.0%, 25.7% vs 14.5%, 26.7% vs 14.5% and 33.3% vs 14.9%, in CSA Leiden, CSA Rotterdam, SONAR, TREAT EARLIER placebo arm). Both ACPA-positive and ACPA-negative CSA patients had a higher frequency of obesity. Within CSA, obesity was not associated with IA development compared to normal weight (pooled effect in meta-analysis of four cohorts HR 1.01 (95% CI 0.93 to 1.08)). CONCLUSIONS: Obesity is not associated with RA development within CSA patients but BMI has already increased in CSA compared to the general population. Obesity, therefore, presumably exerts its risk effect at an early asymptomatic phase of RA development, rather than being associated with the disease processes that ultimately result in clinical arthritis.

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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Improving our understanding of the paradoxical protective effect of obesity on radiographic damage: a large magnetic resonance imaging-study in early arthritis.

OBJECTIVE: Obesity conveys a risk for RA development, while paradoxically, associating with less radiographic progression after RA diagnosis. Using MRI we can study this surprising association in detail from MRI-detected synovitis and osteitis to MRI-detected erosive progression, which precedes radiographic progression. Previous research suggested obesity associates with less osteitis and synovitis. We therefore aimed to (i) validate the previously suggested association between BMI and MRI-detected osteitis/synovitis; (ii) study whether this is specific for ACPA-positive or ACPA-negative RA or also present in other arthritides; (iii) study whether MRI-detected osteitis associates with MRI-detected erosive progression; and (iv) study whether obesity associates with MRI-detected erosive progression. METHODS: We studied 1029 early arthritis patients (454 RA, 575 other arthritides), consecutively included in Leiden Early Arthritis Clinic. At baseline patients underwent hand-and-foot MRI that were RAMRIS-scored, and 149 RA patients underwent follow-up MRIs. We studied associations between baseline BMI and MRI-detected osteitis/synovitis (using linear regression), and erosive progression (using Poisson mixed models). RESULTS: In RA, higher BMI associated with less osteitis at disease onset (ß = 0.94; 95% CI: 0.93, 0.96) but not with synovitis. Higher BMI associated with less osteitis in ACPA-positive RA (ß = 0.95; 95% CI: 0.93, 0.97), ACPA-negative RA (ß = 0.97; 95% CI: 0.95, 0.99) and other arthritides (ß = 0.98; 95% CI: 0.96, 0.99). Over 2 years, overweight and obesity associated with less MRI-detected erosive progression (P = 0.02 and 0.03, respectively). Osteitis also associated with erosive progression over 2 years (P < 0.001). CONCLUSIONS: High BMI relates to less osteitis at disease onset, which is not confined to RA. Within RA, high BMI and less osteitis associated with less MRI-detected erosive progression. This suggests that the protective effect of obesity on radiographic progression is exerted via a path of less osteitis and subsequently fewer MRI-detected erosions.

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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Antibodies against advanced glycation end-products and malondialdehyde-acetaldehyde adducts identify a new specific subgroup of hitherto patients with seronegative arthritis with a distinct clinical phenotype and an HLA class II association.

OBJECTIVE: In rheumatoid arthritis (RA) around two-thirds of patients are autoantibody positive for rheumatoid factor, anti-citrullinated protein antibodies and/or anti-carbamylated protein antibodies. The remaining seronegative subgroup of patients is clinically heterogeneous and thus far, biomarkers predicting the disease course are lacking. Therefore, we analysed the value of other autoantibodies in RA directed against malondialdehyde-acetaldehyde adducts (MAA) and advanced glycation end-products (AGE). METHODS: In sera of 648 patients with RA and 538 patients without RA from the Leiden Early Arthritis Clinic, anti-MAA and anti-AGE IgG antibody levels were measured using ELISA. Associations between genetic risk factors, acute phase reactants, radiological joint damage, remission and anti-PTM positivity were investigated using regression, correlation and survival analyses. RESULTS: Anti-AGE and anti-MAA were most prevalent in RA (44.6% and 46.1% respectively) but were also present in non-RA arthritis patients (32.9% and 30.3% respectively). Anti-AGE and anti-MAA antibodies were associated with HLA-DRB1*03 within seronegative RA (OR=1.98, p=0.003, and OR=2.37, p<0.001, respectively) and, for anti-AGE also in non-RA arthritis patients (OR=2.34, p<0.001). Presence of anti-MAA antibodies was associated significantly with markers of inflammation, erythrocyte sedimentation rate and C reactive protein, in all groups independent of anti-AGE. Interestingly, the presence of anti-AGE and anti-MAA antibodies was associated with radiological progression in patients with seronegative RA, but not evidently with sustained drug-free remission. CONCLUSIONS: Anti-AGE and anti-MAA were present in around 45% of RA patients and 30% of non-RA arthritis patients, and although not specific for RA, their presence associated with HLA, inflammation and, for RA, with clinical outcomes especially in patients with seronegative RA.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Distinction and prognosis of early arthritis phenotypes: an analysis in three European cohorts.

OBJECTIVES: The objective of this study is to evaluate whether there are differences in the long-term prognosis across various phenotypes of early arthritis (EA). METHODS: Three EA cohorts (Reade, Etude et Suivi des Polyarthrites Indifférenciées Récentes (ESPOIR) and Early Arthritis Clinic (EAC)) were analysed. Clinical data were collected up to 24 years. Hands and feet radiographs were scored according to the Sharp van der Heijde (SvdH) method. Latent class analysis was applied to determine the EA phenotypes at baseline. Each class received a label reflecting its most prominent features. Prognostic outcomes included Health Assessment Questionnaire (HAQ), Short Form 36 (SF36) and SvdH score. The association between class membership and outcomes over time was tested in multivariable models. RESULTS: In total, 390 (Reade), 798 (ESPOIR) and 3991 (EAC) patients were analysed separately. Two classes with symmetrical polyarthritis emerged; one of these labelled as autoimmune inflammatory polyarthritis (AIPA), had high likelihood of acute phase reactants (APR) elevation and autoantibody positivity, while the other (mild-inflammatory polyarthritis; MIPA) had not. A third class had oligoarthritis of upper limbs (OAUL) and could be subdivided into autoimmune OAUL and mild-inflammatory OAUL. A fifth class had oligoarthritis of lower limbs. The SvdH scores were worse in patients with APR/autoantibodies (AIPA) than in those without (MIPA). No clinically meaningful differences across classes in HAQ or SF36 over time were found. CONCLUSION: Radiographic progression over time primarily occurs in EA patients with APR/autoantibodies. The absence of these markers, however, does not necessarily translate into better long-term function and quality of life. Clinicians should not only aim at preventing joint damage, but look beyond structural progression in order to further improve the lives of people with EA.