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Objectives To investigate whether biomarkers are modulated by prednisolone treatment in patients with hand OA and whether they can predict response to prednisolone. Methods Biomarkers reflecting tissue turnover and inflammation [aggrecanase-derived neoepitope of arggecan (ARGS), MMP-derived neoepitope of type I collagen (C1M), MMP-derived neoepitope of type III collagen (C3M), marker of true type V collagen formation (PROC5), MMP-derived neoepitope of CRP (CRPM), citrullinated vimentin fragment (VICM), high-sensitivity (hsCRP)] were measured in sera from 78 patients with painful inflammatory hand OA, who were randomized between prednisolone or placebo treatment. Association of baseline biomarker levels with disease characteristics [visual analogue scale (VAS) pain, synovial thickening ultrasonography sum score and erosive OA] and OMERACT-Osteoarthritis Research Society International (OARSI) response after 6 weeks were analysed with linear or logistic regression and adjusted for age, BMI and sex. Change in biomarker levels after 6 weeks was assessed with linear regression adjusted for baseline biomarker levels, age, BMI and sex. Results For all patients (mean age 64 years, 79% female), there were no associations between biomarker levels and VAS finger pain or synovial thickening score at baseline. Patients with erosive hand OA had higher levels of C1M and hsCRP [adjusted geometric mean ratio 1.24 (95% CI 1.03, 1.49) and 1.91 (1.19, 3.06), respectively]. Biomarker levels did not decrease over time. There was no association between baseline biomarkers levels and OARSI response, except for CRPM [geometric mean ratio of 0.88 (0.77, 1.00)]. Conclusion Erosive disease was associated with higher levels of C1M and hsCRP. Biomarker levels were not influenced by treatment with prednisolone. Current biomarkers were not associated with response to prednisolone in hand OA.

Objectives To investigate pain, pain trajectories and their determinants in hand osteoarthritis (OA). Methods Data from the HOSTAS (Hand OSTeoArthritis in Secondary care) consisting of consecutive hand OA patients were used. Australian Canadian Osteoarthritis Hand Index (AUSCAN) pain was measured yearly for four years. Patients with complete AUSCAN at ≥2 time points were eligible for longitudinal analysis. Associations between variables of interest and baseline AUSCAN pain were investigated with linear regression. Development of pain over time was modelled using latent class growth analysis (LCGA). Associations of LCGA classes with variables of interest were analysed using multinomial logistic regression adjusted for baseline pain. Results A total of 484/538 patients [mean (s.d.) age 60.8 (8.5) years, 86% women, mean (s.d.) AUSCAN pain 9.3 (4.3)] were eligible for longitudinal analysis. Sex, marital and working status, education, disease duration and severity, anxiety and depression scores, lower health-related quality of life (HR-QoL), specific illness perceptions and coping styles were associated with baseline pain. LCGA yielded three classes, characterized by average pain levels at baseline; average pain remained stable over time within classes. Classes with more pain were positively associated with BMI, tender joint count, symptom duration, hand function scores and depression scores, negatively with physical HR-QoL, and education level. Conclusion Baseline pain was associated with patient and disease characteristics, and psychosocial factors. LCGA showed three pain trajectories in hand OA patients, with different baseline pain levels and stable pain over time. Classes were distinguished by BMI, education level, disease severity, depression and HR-QoL.

Hand osteoarthritis (OA) is treated by several medical professionals. In this review the rheumatologist's perspective will be conveyed. The rheumatologist tasks are to diagnose hand OA, exclude other causes of patient's complaints, and provide treatment. The rheumatologist therefore has a distinctive and important role in hand OA treatment. Although no disease modifying treatment exists, there are multiple options for managing hand OA in rheumatology practice, with the goal of achieving symptom relief and optimizing hand function. These treatments can be non-pharmacological or pharmacological. In this review we will provide a summary of evidence-based management options based on existing guidelines. Furthermore, we will describe common practice among rheumatologists for hand OA management. In order to do so, we performed a literature review of studies addressing treatment modality usage for hand OA. The review comprised 25 studies, which were heterogeneous in terms of treatment modality usage. In addition, a detailed description of care usage by patients in a Rheumatology outpatient clinic is given, based on data of our Hand OSTeoArthritis in Secondary care primary hand OA cohort. The large majority of these patients used any form of hand OA treatment (83%). Non-pharmacological treatment was less frequently used (47%) than pharmacological treatment (77%).(c) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )

ObjectivesData on work participation impairment and related societal costs for patients with hand osteoarthritis (OA) are scarce. Therefore, we aimed to investigate the association of hand OA with work limitations and costs of productivity loss in paid and unpaid work.MethodsWe used data from the Hand Osteoarthritis in Secondary Care cohort, including patients with hand OA diagnosed by their treating rheumatologist. Using the validated Health and Labour Questionnaire, we assessed experienced unpaid and paid work restrictions, unpaid work replacement by others and inefficiency and absence during paid work related to hand OA over the last 2 weeks. Societal costs (€) per hour of paid and unpaid work were estimated using Dutch salary data in 2019.Results381 patients were included (mean age 61 years, 84% women, 26% high education level, 55% having any comorbidity). Replacement of unpaid work by others due to hand OA was necessary for 171 out of 381 patients (45%). Paid work was reported by 181/381 patients (47%), of whom 13/181 (7%) reported absenteeism, 28/181 (15%) unproductive hours at work and 120/181 (66%) paid work restrictions due to hand OA.Total estimated work-related societal costs per patient with hand OA (381 patients) were €94 (95% CI 59 to 130) per 2 weeks (€2452, 95% CI 1528 to 3377 per year).ConclusionsHand OA is associated with impairment in paid and unpaid work participation, which translates into substantial societal costs of lost productivity. These results highlight the importance of adequate hand OA treatment.

ObjectivesPorphyromonas gingivalis (P.g.) is discussed to be involved in triggering self-reactive immune responses. The aim of this study was to investigate the autocitrullinated prokaryotic peptidylarginine deiminase (PPAD) from P.g. CH2007 (RACH2007-PPAD) from a rheumatoid arthritis (RA) patient and a synthetic citrullinated PPAD peptide (CPP) containing the main autocitrullination site as potential targets for antibody reactivity in RA and to analyse the possibility of citrullinating native human proteins by PPAD in the context of RA.MethodsRecombinant RACH2007-PPAD was cloned and expressed in Escherichia coli. Purified RACH2007-PPAD and its enzymatic activity was analysed using two-dimensional electrophoresis, mass spectrometry, immunoblot and ELISA. Autoantibody response to different modified proteins and peptides was recorded and bioinformatically evaluated.ResultsRACH2007-PPAD was capable to citrullinate major RA autoantigens, such as fibrinogen, vimentin, hnRNP-A2/B1, histone H1 and multiple peptides, which identify a common RG/RGG consensus motif. 33% of RA patients (n=30) revealed increased reactivity for α-cit-RACH2007-PPAD before RA onset. 77% of RA patients (n=99) presented α-cit-specific signals to CPP amino acids 57–71 which were positively correlated to α-CCP2 antibody levels. Interestingly, 48% of the α-CPP-positives were rheumatoidfactor IgM/anti-citrullinated peptide/protein antibodies (ACPA)-negative. Anti-CPP and α-RACH2007-PPAD antibody levels increase with age. Protein macroarrays that were citrullinated by RACH2007-PPAD and screened with RA patient sera (n=6) and controls (n=4) uncovered 16 RACH2007-PPAD citrullinated RA autoantigens and 9 autoantigens associated with lung diseases. We showed that the α-CPP response could be an important determinant in parenchymal changes in the lung at the time of RA diagnosis (n=106; p=0.018).ConclusionsRACH2007-PPAD induced internal citrullination of major RA autoantigens. Anti-RACH2007-PPAD correlates with ACPA levels and interstitial lung disease autoantigen reactivity, supporting an infection-based concept for induction of ACPAs via enzymatic mimicry.

Background: Pain is common in hand osteoarthritis (OA) and multiple types may occur. We investigated the prevalence, associated patient characteristics, influence on health-related quality of life (HR-QoL) and response to anti-inflammatory treatment of neuropathic-like pain in inflammatory hand OA. Methods: Data were analysed from a 6-week, randomized, double-blind, placebo-controlled trial investigating prednisolone treatment in 92 patients with painful inflammatory hand OA. Neuropathic-like pain was measured with the painDETECT questionnaire. Associations between baseline characteristics and baseline neuropathic-like pain were analysed with ordinal logistic regression, association of baseline neuropathic-like pain symptoms with baseline HR-QoL with linear regression, painDETECT and visual analogue scale (VAS) change from baseline to week 6 and interaction of painDETECT with prednisolone efficacy on VAS pain change from baseline to week 6 with generalized estimating equations (GEE). Results: Of 91 patients (79% female, mean age 64) with complete painDETECT data at baseline, 53% were unlikely to have neuropathic-like pain, 31% were indeterminate and 16% were likely to have neuropathic-like pain. Neuropathic-like pain was associated with female sex, less radiographic damage and more comorbidities. Patients with neuropathic-like pain had lower HR-QoL (PCS-6.5 [95% CI −10.4 to −2.6]) than those without. Neuropathic-like pain symptoms remained under prednisolone treatment and no interaction was seen between painDETECT and prednisolone efficacy on VAS pain. Conclusions: In this study, 16% of inflammatory hand OA patients had neuropathic-like pain. They were more often female, had more comorbidities and had lower QoL than those without. Neuropathic-like pain symptoms remained despite prednisolone treatment and did not seem to affect the outcome of prednisolone treatment. Significance: Pain is the dominant symptom in hand OA, with an unclear aetiology. In this study, we found that neuropathic-like pain may play a role in hand OA, that it showed associations with female sex, younger age and more comorbidities and that it lowered health-related quality of life in hand OA. Neuropathic-like pain in hand OA seems resistant to prednisolone therapy but did not seem to interfere with the treatment of inflammatory pain with prednisolone.

Objectives Agreement between real-time and static ultrasonography has not been studied in musculoskeletal diseases. We studied this agreement in inflammatory hand OA. Methods Ultrasonography was performed blinded to clinical information of 30 joints of 75 patients with hand OA, treated with prednisolone in a randomized placebo-controlled double-blind trial. Images were scored real-time at acquisition and stored images were scored static (paired in known chronological order) for inflammatory features and osteophytes (score 0–3). Agreement between methods was studied at joint level with quadratic weighted kappa. At patient level intra-class correlations (ICC) of sum scores and change in sum-scores (delta baseline—week 6) were calculated. Responsiveness of scoring methods was analysed with generalized estimating equations (GEE) with treatment as independent and ultrasonography findings as dependent variable. Results Agreement at baseline was good to excellent at joint level (kappa 0.72–0.88) and moderate to excellent at patient level (ICC 0.58–0.91). Agreement for change in sum scores was poor to fair for synovial thickening and effusion (ICC 0.18 and 0.34, respectively), while excellent for Doppler signal (ICC 0.80). Real-time ultrasonography discriminated between prednisolone and placebo with a mean between-group difference of synovial thickening of −2.5 (95% CI: −4.7, −0.3). Static ultrasonography did not show a decrease in synovial thickening. Conclusion While cross-sectional agreement between real-time and static ultrasonography is good, static ultrasonography measurement of synovial thickening did not show responsiveness to prednisone therapy while real-time ultrasonography did. Therefore, when ultrasonography is used in clinical trials, real-time dynamic scoring should remain the standard for now.

The use of assays to detect anti-citrullinated protein antibodies (ACPAs) is helpful in the diagnosis of rheumatoid arthritis. But how good are these assays at detecting ACPAs and do we really know what the results are telling us about ACPA specificity?

Objectives: To explore the impact on daily life of symptoms experienced by those with systemic autoimmunity associated with rheumatoid arthritis (RA). Methods: Fifteen people took part in focus groups to explore the impact of symptoms on daily life. Results: Core themes included: 1) physical impact of limited hand function and mobility; 2) psychological distress experienced included a fear of symptoms progressing into RA, uncertainty about the future, feelings of despair, shame and frustration. Conclusion: People with arthralgia at risk of developing RA experienced considerable physical and psychological impact of symptoms. Greater consideration should be given to the needs of people at risk of developing RA.

Objective Studies on the role of psychosocial vulnerability in the development of arthritis must be performed early in the disease course to exclude the reverse explanation that arthritis leads to psychological symptoms. Therefore, the objective of this study was to investigate the longitudinal (5-year) association between depressive mood, daily stressors, avoidance coping and social support as predictors, and the development of arthritis and other clinical parameters as outcomes, in persons with seropositive arthralgia at risk of developing rheumatoid arthritis. Methods Five-year follow-up data of 231 patients from the Reade seropositive arthralgia cohort were used. Clinical and psychological data were collected using physical examinations and questionnaires. Mixed models and Cox regression analyses were used to assess the 5-year associations between depressive mood, daily stressors, avoidance coping or social support, and the development of arthritis or clinical parameters (tender joint count, Visual Analogue Scale (VAS) pain, VAS morning stiffness and erythrocyte sedimentation rate (ESR)). Results Higher scores for depressive mood and lower scores for social support were not associated with the development of arthritis nor with ESR. However, they were longitudinally associated with an increase in pain (p

Objective In rheumatoid arthritis (RA), autoantibodies such as anti–citrullinated protein antibodies (ACPAs) develop in response to neoepitopes that are formed under conditions of chronic inflammation. These autoantibodies may subsequently be fragmented by inflammation-associated proteases, leading to the formation of F(ab′)2 fragments. The hinge of F(ab′)2 fragments can serve as a neoepitope, and so-called antihinge antibodies (AHAs) can be found in RA patients, which might modulate the function of (fragmented) autoantibodies. We undertook this study to investigate the presence and specificities of AHAs in different stages of RA and to study their function. Methods The presence of AHAs was assessed by radioimmunoassay in healthy controls, blood donors who later developed RA, patients with arthralgia, patients with early RA, and patients with established RA. Specificity of the AHAs was analyzed with inhibition assays, and complement-activating ability was studied with a C4b deposition assay. Results Antibodies to IgG1 hinge, IgG2 hinge, and IgG4 hinge were detected in patients with established RA, with anti–IgG4 hinge antibodies being most specific (appearing in 1% of healthy controls, 3.8% of blood donors who later developed RA, 13% of arthralgia patients, 19% of early RA patients, and 16% of established RA patients). Anti–IgG4 hinge antibodies were subclass specific and were able to restore C4b deposition by IgG4 F(ab′)2 fragments. In patients with arthralgia and patients with early RA, anti–IgG4 hinge antibodies were associated with rheumatoid factors and ACPAs. Conclusion Anti–IgG4 hinge antibodies are present in RA patients and have low sensitivity but high specificity for RA. Since a significant proportion of ACPAs can be of the IgG4 subclass, the formation of anti–IgG4 hinge antibodies may represent one mechanism of ACPA-mediated inflammation.

The aim of this study was to explore symptoms and symptom development during the earliest phases of RA in patients with seropositive arthralgia and patients newly diagnosed with RA.Interviews were conducted with 15 seropositive patients (anti-CCP positive, and often with arthralgia) and 11 newly presenting RA patients [classified according to the 2010 ACR/European League Against Rheumatism (EULAR) criteria]. Feedback procedures shared the experiences of seropositive arthralgia patients with early RA patients and vice versa. Data were analysed using thematic analysis.Symptoms common to both groups included joint pain, psychological distress, muscle cramps, abnormal skin sensations, stiffness, loss of motor control, weakness, fatigue and sleeping difficulties. Also, patterns of symptom evolution and the order of symptom development were described. Seropositive arthralgia patients described pain as annoying, while RA patients described how the severity of pain intensified before diagnosis, to the point where symptoms were psychologically distressing. Patients with seropositive arthralgia described reddening of the skin and burning sensations that they felt were indicative of the onset of swelling. Intense pain appeared to precede the onset of swelling for those with RA, which was often palindromic and travelled between joints until it later became persistent.This study highlights the breadth of symptoms that constitute the earliest phases of RA. Further research is needed to develop measures of symptom patterns and clusters to allow the predictive utility of symptoms to be assessed and to allow the integration of aspects of the patient's history into evidence-based investigative and management algorithms for use in primary and secondary care.

Objective Recently, we discovered a new autoantibody system in rheumatoid arthritis (RA): anti–carbamylated protein (anti-CarP) antibodies. These antibodies have value in predicting joint destruction; however, it is not clear whether they are present before the diagnosis of RA and whether they have value as predictors of RA development. Therefore, we studied whether anti-CarP antibodies are present in patients with arthralgia and whether their presence is associated with the development of RA. Methods Sera from 340 arthralgia patients who did not have clinical signs of arthritis but who were positive for IgM rheumatoid factor (IgM-RF) and/or anti–cyclic citrullinated peptide 2 (anti–CCP-2) and 32 healthy controls were tested for anti-CarP IgG antibodies. Of the patients with arthralgia, 111 were IgM-RF positive/anti–CCP-2 antibody negative and 229 were anti–CCP-2 antibody positive. Patients were observed for the development of RA (based on the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria) during a median followup period of 36 months. Cox proportional hazards regression analysis was performed to compare the risk of developing RA between arthralgia patients who were positive for anti-CarP antibodies and those who were negative for anti-CarP antibodies during followup. Results Anti-CarP antibodies were present in the sera of 39% of the patients. One hundred twenty patients developed RA, after a median of 12 months (interquartile range [IQR] 6–24). The presence of anti-CarP antibodies was associated with the development of RA in the entire arthralgia cohort after correction for RF and anti–CCP-2 antibody status (hazard ratio 1.56 [95% confidence interval 1.06–2.29], P = 0.023), as well as in the anti–CCP-2 antibody–positive subgroup (odds ratio 2.231 [95% confidence interval 1.31–3.79], P = 0.003). Conclusion Anti-CarP antibodies are present in patients with arthralgia, and their presence predicts the development of RA independent of anti–CCP-2 antibodies.

To validate the presence and demonstrate the clinical value of the type I interferon (IFN)-signature during arthritis development.In 115 seropositive arthralgia patients who were followed for the development of arthritis (Amsterdam Reade cohort), and 25 presymptomatic individuals who developed rheumatoid arthritis (RA) later, and 45 population-based controls (Northern Sweden cohort), the expression levels of 7 type I IFN response genes were determined with multiplex qPCR and an IFN-score was calculated. The diagnostic performance of the IFN-score was evaluated using Cox regression and Receiver Operating Characteristics (ROC)-curve analysis.In 44 of the 115 at-risk individuals (38%) from the Amsterdam Reade cohort, arthritis developed after a median period of 8 months (IQR 5-13). Stratification of these individuals based on the IFN-score revealed that 15 out of 25 IFN(high) individuals converted to arthritis, compared with 29 out of 90 IFN(low) individuals (p=0.011). In the Northern Sweden cohort, the level of the IFN-score was also significantly increased in presymptomatic individuals who developed RA compared with population-based controls (p=0.002). Cox regression analysis of the Amsterdam Reade cohort showed that the hazard ratio (HR) for development of arthritis was 2.38 (p=0.008) for IFN(high) at-risk individuals after correction for anticitrullinated protein antibodies (ACPA) and rheumatoid factor (RF). The ROC-curve area under the curve (AUC) for the IFN-score combined with ACPA and RF in the prediction of arthritis was 78.5% (p=0.0001, 95% CI 0.70 to 0.87).The results demonstrated clinical utility for the IFN-signature as a biomarker in the prediction of arthritis development.

Objective. ACPAs are thought to play a pathogenic role in RA. Because of their polyclonal nature it is difficult to study characteristics of ACPAs such as cross-reactivity or affinity. This study aimed to analyse the ACPA response at clonal level. Methods. Citrullinated fibrinogen-specific B cells were isolated from blood derived from an RA patient by fluorescent automated cell sorting (FACS). Antigen specificity was verified by ELISA of culture supernatant. RNA of antigen-specific B cells was isolated and VH and VL chains were cloned and subsequently expressed as IgG1 antibodies. Results. Two human recombinant antibodies were obtained that bind to citrullinated fibrinogen peptide (cFib). Both monoclonal antibodies originate from different naive B cells, undergo extensive somatic hypermutation and bind to cFib (but not to Fib) with moderate avidity. Furthermore, they show distinct cross-reactivity patterns towards other citrullinated peptides, suggesting that both antibodies have different primary targets. Conclusion. Together these data suggest that ACPAs are formed by antigen-driven maturation, and that multiple citrullinated antigens are involved in activating the B-cell response.

OBJECTIVES: /st> To determine the fine specificity of anti-citrullinated protein antibodies (ACPA) in the early phase of arthritis development, the ACPA repertoire in arthralgia patients and the association with arthritis development were studied. METHODS: /st> A total of 244 patients with arthralgia positive for anti-cyclic citrullinated peptide antibodies (aCCPs) and/or IgM rheumatoid factor (IgM-RF), without arthritis were included. Development of arthritis was defined as presence of one or more swollen joints at clinical examination during follow-up. Sera were tested at baseline for reactivity to five citrullinated peptides derived from fibrinogen (three), vimentin (one) and α-enolase (one) and five corresponding arginine peptides in an ELISA. RESULTS: /st> In all, 69 patients (28%) developed arthritis in a median of 3 joints after a median follow-up of 11 (IQR 5-20) months. Reactivity to each peptide was significantly associated with arthritis development (p Arthritis development is not associated with recognition of a specific citrullinated peptide once joint complaints are present. The ACPA repertoire in some patients with arthralgia is expanded. High aCCP levels are associated with a qualitatively broad ACPA repertoire. Patients with an extended ACPA repertoire have a higher risk of developing arthritis

Clinical studies point towards an association between periodontitis and rheumatoid arthritis (RA).1 ,2 A pathogenic role is suggested for Porphyromonas gingivalis .3 P gingivalis may contribute to the pathogenesis of RA by breaking immune tolerance through formation of (bacterial and human) citrullinated proteins, leading to anticitrullinated protein antibody production (ACPA).4 ,5 Since ACPA production precedes RA development6 and because P gingivalis IgG antibodies are long-term stable in untreated periodontitis patients,7 we investigated whether anti- P gingivalis antibody levels are prognostic for development of RA, by assessing these antibodies in a cohort of 289 adults at risk for RA. Patients with arthralgia and seropositivity for IgM-rheumatoid factor (IgM-RF) and/or ACPA were selected from a prospective follow-up study on arthritis development.8 They are further referred to as seropositive arthralgia patients (SAP); their median follow-up was 30 months (IQR 13–49). Baseline sera were used for measurement of ACPA, IgM-RF, C-reactive protein (CRP) and HLA-DRB1 SE carrier status.8 IgA, IgG and IgM antibody levels against P gingivalis were determined by in-house ELISA with a pooled lysate of clinical isolates of P gingivalis as …

Early recognition followed by treatment of rheumatoid arthritis (RA) helps to maintain joint integrity and functional capacity,1 suggesting it may be beneficial to intervene in patients with arthralgia before RA develops. Anticitrullinated protein antibodies (ACPA) and rheumatoid factor (RF) are established predictive markers,2 ,3 but only 20–40% of ACPA and/or RF positive patients with arthralgia develop RA within 2 years.4 Recently, we have demonstrated that the type I interferon (IFN) signature correctly identifies 52% of patients with arthralgia who will develop RA within 2 years.5 ,6 Our previous study suggested that a B cell related gene signature was associated with protection against arthritis development,6 and could aid in the prediction of arthritis development. We therefore studied the clinical value of the B cell signature, comprising CD19, CD20, CD79α and CD79β, for the prediction of arthritis development in an independent cohort of 115 ACPA and/or RF positive patients with arthralgia followed for median 22 months5 and explored the phenotypical nature of this B cell signature. In total, 44 patients (38%) developed arthritis (defined as one or more swollen joints) within 2 years. Of these, 4 patients had undifferentiated arthritis and 40 patients fulfilled the 2010 American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) criteria for RA. Patients were stratified into B cellhigh …

ObjectiveTo determine whether anticitrullinated protein antibodies (ACPA) exhibit specific changes in Fc glycosylation prior to the onset of arthritis.MethodsSerum samples of patients with ACPA-positive arthralgia (n=183) were collected at baseline and at various time points of follow-up. 105 patients developed arthritis after a median of 12 months (IQR 6–24) and were classified as having either rheumatoid arthritis (RA, n=48) or undifferentiated arthritis (UA, n=57) based on the 1987 American College of Rheumatology (ACR) criteria. ACPA and total serum IgG were isolated by affinity purification and cleaved by trypsin. ACPA-IgG1 Fc-glycopeptides were subsequently analysed by nano-liquid chromatography mass spectrometry and compared to those of total IgG1.ResultsAt baseline, ACPA-IgG1 and total IgG1 from arthralgia patients displayed similar Fc glycosylation patterns. By contrast, at the onset of arthritis, ACPA exhibited a decrease in galactose residues in RA patients, but not in UA patients. This decrease occurred around 3 months prior to diagnosis and was paralleled by an increase in systemic inflammation (erythrocyte sedimentation rate). Galactosylation of total IgG1 was also decreased in RA, but this did not precede the onset of arthritis. Interestingly, we additionally noted a higher degree of ACPA-IgG1 Fc core fucosylation at baseline as compared with total IgG1, which further increased prior to diagnosis.ConclusionsACPA display significant changes in Fc galactosylation and fucosylation prior to the onset of RA. These changes towards a more pro-inflammatory phenotype could be involved in driving the disease process.

Objective The presence of anti-citrullinated protein antibodies (ACPA) and IgM-rheumatoid factor (IgM-RF) years before the clinical diagnosis of rheumatoid arthritis (RA) suggests they are possibly involved in the pathogenic process underlying RA. In this study, we analysed whether anti-carbamylated protein (anti-CarP) antibodies, a novel autoantibody system against carbamylated proteins, can also be detected in healthy individuals before they developed RA. Methods Multiple sera from asymptomatic blood donors prior to the onset of their RA symptoms and sera from age-matched and sex-matched controls were tested for the presence of antibodies directed against carbamylated-fetal calf serum (Ca-FCS), carbamylated-fibrinogen (Ca-Fib), cyclic citrullinated-peptide 2 and IgM-RF. Results Anti-Ca-FCS and anti-Ca-Fib antibodies were each present in 27% and 38% of the last serum samples of blood donors prior to the diagnosis of RA. Both anti-Ca-FCS and anti-Ca-Fib antibodies could be detected many years before the onset of RA. Anti-CarP antibodies as well as ACPA are, on average, detected earlier than IgM-RF. Conclusions In addition to ACPA and IgM-RF, also the newly identified anti-CarP antibodies appear many years before the diagnosis of RA.

Objectives Millions of patients worldwide are treated with therapeutic monoclonal antibodies. These biological therapeutics can be immunogenic, resulting in anti-drug antibody formation which leads to loss of response. Fully human biological agents, such as the anti-tumour necrosis factor α (anti-TNFα) antibody adalimumab, are considered to be weakly immunogenic, but anti-adalimumab antibodies (AAA) were recently detected in more than half of treated patients with rheumatoid arthritis (RA) within 28 weeks of treatment. A study was undertaken to determine the mechanism by which AAA lead to loss of response. Methods The specificity of the repertoire of AAA was investigated in a cohort of 50 AAA-positive RA patients. Inhibition experiments using TNFα and patient-derived anti-adalimumab monoclonal antibodies were performed. Results The antibody response against adalimumab is highly restricted: Fab fragments of a single monoclonal antibody specific for the idiotype of adalimumab inhibited 98.65% (25th–75th percentiles: 98.25–99.90) of the total anti-adalimumab reactivity in serum from 50 AAA-positive patients. The anti-adalimumab response was confined to the TNFα binding region of adalimumab, thereby neutralising its therapeutic efficacy. In line with this restricted specificity, small immune complexes were found in the circulation of AAA-forming patients. Conclusions The humoral immune response against adalimumab is highly restricted and limited to the idiotype of the therapeutic antibody. All antibodies result in functional neutralisation of the drug, thereby providing a mechanism by which AAA formation leads to clinical non-response.

ObjectiveTo predict the development of arthritis in anticyclic citrullinated peptide antibodies and/or IgM rheumatoid factor positive (seropositive) arthralgia patients.MethodsA prediction rule was developed using a prospective cohort of 374 seropositive arthralgia patients, followed for the development of arthritis. The model was created with backward stepwise Cox regression with 18 variables.Results131 patients (35%) developed arthritis after a median of 12 months. The prediction model consisted of nine variables: Rheumatoid Arthritis in a first degree family member, alcohol non-use, duration of symptoms ConclusionsIn patients presenting with seropositive arthralgia, the risk of developing arthritis can be predicted. The prediction rule that was made in this patient group can help (1) to inform patients and (2) to select high-risk patients for intervention studies before clinical arthritis occurs.

Recently, we discovered a new autoantibody system in rheumatoid arthritis (RA): anti-carbamylated protein (anti-CarP) antibodies. These antibodies have value in predicting joint destruction; however, it is not clear whether they are present before the diagnosis of RA and whether they have value as predictors of RA development. Therefore, we studied whether anti-CarP antibodies are present in patients with arthralgia and whether their presence is associated with the development of RA.Sera from 340 arthralgia patients who did not have clinical signs of arthritis but who were positive for IgM rheumatoid factor (IgM-RF) and/or anti-cyclic citrullinated peptide 2 (anti-CCP-2) and 32 healthy controls were tested for anti-CarP IgG antibodies. Of the patients with arthralgia, 111 were IgM-RF positive/anti-CCP-2 antibody negative and 229 were anti-CCP-2 antibody positive. Patients were observed for the development of RA (based on the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria) during a median followup period of 36 months. Cox proportional hazards regression analysis was performed to compare the risk of developing RA between arthralgia patients who were positive for anti-CarP antibodies and those who were negative for anti-CarP antibodies during followup.Anti-CarP antibodies were present in the sera of 39% of the patients. One hundred twenty patients developed RA, after a median of 12 months (interquartile range [IQR] 6-24). The presence of anti-CarP antibodies was associated with the development of RA in the entire arthralgia cohort after correction for RF and anti-CCP-2 antibody status (hazard ratio 1.56 [95% confidence interval 1.06-2.29], P=0.023), as well as in the anti-CCP-2 antibody-positive subgroup (odds ratio 2.231 [95% confidence interval 1.31-3.79], P=0.003).Anti-CarP antibodies are present in patients with arthralgia, and their presence predicts the development of RA independent of anti-CCP-2 antibodies.

Objective.To evaluate whether markers of the acute-phase response in patients presenting with arthralgia and positive anticitrullinated protein antibodies (ACPA) and/or immunoglobulin M rheumatoid factor (IgM-RF) could be predictive for the development of arthritis.Methods.In total, 137 ACPA- and/or IgM-RF-positive patients were included. Patients were followed annually for the development of arthritis, defined as presence of 1 or more swollen joints at clinical examination. High-sensitivity C-reactive protein (hsCRP), procalcitonin (PCT), secretory phospholipase A2 (SPLA2), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), IL-12p70, IL-10, and interferon-γ (IFN-γ) were measured in baseline serum samples. Gene expression focusing on a predefined panel of genes coding for inflammatory molecules was measured by multiplex ligation-dependent probe amplification.Results.Thirty-five patients (26%) developed arthritis within a median time of 11 months (interquartile range 3.7–18 mo). Circulating levels of cytokines, SPLA2, hsCRP, and PCT were not different between patients with progression to clinical arthritis and those without progression. However, a trend for IL-12p70, TNF-α, IL-10, IL-6, and SPLA2 was observed. No correlation between messenger RNA (mRNA) expression levels of inflammatory genes and progression to arthritis was found. Subgroup analysis of patients with early progression to arthritis showed higher levels of mRNA expression of poly(A)-specific ribonuclease and polycomb complex protein BMI-1 compared to patients without progression to arthritis.Conclusion.Although low-grade inflammation is present before onset of clinical arthritis in large cohorts and can be detected using consecutive measurements, a single measurement of acute-phase reactants seems to have limited value for prediction of development of arthritis in individual patients.

Introduction: Ultrasonography (US) has better sensitivity than clinical evaluation for the detection of synovitis in early rheumatoid arthritis (RA). Patients presenting with arthralgia and a positive anti-citrullinated protein antibodies (ACPA) and/or Rheumatoid Factor (IgM-RF) status are at risk for developing RA. In the present study, US utility and predictive properties in arthralgia patients at risk for the development of arthritis were studied. Methods: 192 arthralgia patients with ACPA and/or IgM-RF were included. Absence of clinical arthritis was confirmed by two physicians. US was performed by one of two trained radiologists of any painful joint, and of adjacent and contralateral joints. Joint effusion, synovitis and power Doppler (PD) signal in the synovial membrane of the joints and tenosynovitis adjacent to the joint were evaluated and classified on a 4-grade semi-quantitative scale. Grade 2-3 joint effusion, synovitis, tenosynovitis and grade 1-3 Power Doppler signal were classified as abnormal. Results: Forty-five patients (23%) developed arthritis after a mean of 11 months. Inter-observer reliability for synovitis and PD was moderate (kappa 0.46, and 0.56, respectively) and for joint effusion low (kappa 0.23). The prevalence of tenosynovitis was too low to calculate representative kappa values. At joint level, a significant association was found between US abnormalities and arthritis development in that joint for joint effusion, synovitis and PD. At patient level, a trend was seen towards more arthritis development in patients who had US abnormalities for joint effusion, synovitis, PD and tenosynovitis. Conclusions: US abnormalities were associated with arthritis development at joint level, although this association did not reach statistical significance at patient level. US could potentially be used as a diagnostic tool for subclinical arthritis in seropositive arthralgia patients. However, further research is necessary to improve test characteristics.

Background A preclinical phase of rheumatoid arthritis (RA) has been recognized in which abnormalities in autoantibodies exist, frequently accompanied by arthralgia. IgM rheumatoid factor (IgM-RF) and anti-citrullinated protein antibodies (ACPA) can be present many years before the diagnosis of RA, and blood donor cohorts show a rise in these markers 1-3 years preceding diagnosis. Objectives The present study was undertaken to develop individual prediction models using the autoantibody levels over time. Methods Data came from 263 patients in an ongoing prospective cohort of arthralgia patients with ACPA and/or IgM-RF positivity and with repeated measurements of ACPA and IgM-RF, who were followed for arthritis development. These patients were used to fit a joint model of IgM-RF/ACPA levels over time combined with time-to-event data for arthritis. Results Ninety-six patients (26%) developed arthritis after a median of 22 months (IQR 15-37). A total of 986 antibody measurements were included with a median number of 4 (IQR 3-5). The course of antibody levels over time was highly variable. On a group level, there was no statistically significant change of RF levels over time between the groups of patients who developed arthritis compared to those who did not. ACPA levels over time on the group level showed a small but statistically significant difference between the groups, with a rise of 10log transformed ACPA of 0.004 per month in the arthritis group and 0 per month in the patients who did not develop arthritis. The combination of longitudinally measured ACPA with time-to-event data for arthritis in the joint models showed a corrected hazard ratio of 2.6 (95%CI: 1.9-3.6, p Conclusions ACPA levels over time had limited additional predictive value over baseline measurement of ACPA levels only, while longitudinally measured RF had no predictive value for development of arthritis in seropositive arthralgia patients. The use of repeated antibody measurements for the individual prediction of arthritis development in the symptomatic at risk phase does not seem useful. Disclosure of Interest None declared

Background and Objective Anti-citrullinated protein antibodies (ACPA) and IgM-rheumatoid factor (IgM-RF) are auto-antibodies that can be detected many years before the clinical diagnosis of rheumatoid arthritis (RA). In recent studies we discovered a novel family of autoantibodies, anti-carbamylated protein (anti-CarP) antibodies. Carbamylation, like citrullination, is a post-translational modification of proteins. We observed that in RA, next to an antibody response against citrullinated proteins, also an immune response against carbamylated proteins exists. These anti-CarP antibodies are of prognostic value in RA as they associate with severe joint destruction in ACPA negative RA. In addition anti-CarP antibodies associate with future development of RA in patients suffering from arthralgia. Here we analysed whether anti-CarP antibodies are already present prior to symptom onset of RA and which auto-antibody appears first over time. Materials and Methods Sera of 79 RA patients prior to diagnosis and 141 age and sex matched controls that were regular blood donors of the Amsterdam Bloodbank (Amsterdam, The Netherlands) were tested for the presence of anti-CarP antibodies, anti-CCP2 antibodies and RF-IgM using sequential pre-RA sera, obtained at 1-2 year intervals. Results Anti-CarP antibodies were present in 39% of the serum samples that were drawn just prior to the diagnosis of RA of blood donors compared to 4% of the matched control samples. Anti-CarP antibodies were present in both ACPA positive and in ACPA negative patients. Of the 79 individuals that developed RA, 42% were positive for anti-CCP2 antibodies and 24% for IgM RF. Analysis of the longitudinal samples revealed a gradual increase in the number of samples positive for anti-CarP antibodies and in the levels of anti-CarP antibodies towards the diagnosis of RA. We observed that anti-CarP antibodies could be detected many years before the onset of symptoms with a median of 8 years and a maximum of 14 years. Comparing the first appearance of the three autoantibody families revealed that both ACPA and anti-CarP antibodies appear earlier than IgM-RF. Conclusions Next to ACPA and IgM-RF also the newly identified anti-CarP antibodies appear many years before the onset of clinical symptoms of RA.

Background/Objective Recently, we discovered a new auto- antibody system in rheumatoid arthritis (RA): anti carbamylated protein antibodies (anti-CarP). These antibodies have additional prognostic value in predicting joint destruction when compared to anti-citrullinated protein antibodies (ACPA). However, it is not yet known whether anti-CarP antibodies are present before the diagnosis of RA and whether they have predictive value for the development of RA. Therefore we studied whether anti-CarP antibodies are present in arthralgia patients and whether their presence associates with the development of RA. Methods Sera of 340 arthralgia patients without clinical signs of arthritis and 32 healthy controls were measured for the presence of anti-CarP IgG antibodies. One hundred eleven arthralgia patients (33%) were IgM-rheumatoid factor (IgM-RF) positive/anti-cyclic citrullinated peptide 2 (aCCP2) negative and 229 (67%) were aCCP2 positive. Patients were followed for the development of RA (2010 criteria). The median follow up time was 36 months. Cox regression analysis was performed to compare the risk of developing RA between Anti-CarP positive and negative arthralgia patients in follow up time. Results The arthralgia cohort consisted of 340 IgM-RF and/or aCCP positive patients. Anti-CarP antibodies were present in sera of 113 (39%) of the tested patients. A total of 120 patients developed RA after a median (IQR) of 12 (6–24) months. The presence of anti-CarP antibodies was associated with the development of RA in the whole arthralgia cohort even after correction for RF and aCCP2 status (HR: 1.56; 95%CI: 1.06–2.29; p = 0.023), as well as in the aCCP2 positive subgroup (OR: 2.231; 95%CI: 1.31–3.79; p = 0.003). Conclusions Anti-CarP antibodies were present in arthralgia patients and their presence predicted the development of RA independent of aCCP2 antibodies. Disclosure These studies were financially supported by Janssen Biologics BV, (Johnson & Johnson).

Background/purpose Early recognition of development of rheumatoid arthritis (RA) allows timely start of treatment. Recently, the authors reported gene signatures in the peripheral blood (PB), involving interferon (IFN) activity and B cell related genes, which are associated with the development of arthritis. The objective of this study is to validate these findings in independent cohorts. Method The authors analysed IFN-response gene expression in PB samples from 40 anticitrullinated protein antibodies (ACPA)+/rheumatoid factor (RF)+arthralgia patients from the Amsterdam Reade cohort who are clinically followed for RA development. In addition, PB mononuclear cells (MCs) of 22 preonset RA, 25 RA patients, and 48 healthy controls (HC) from the Northern Sweden Population Repository (Umea University) were studied. Fluorescence-activated cell sorting (FACS)-analysis for B cell marker expression was performed on PB from 87 ACPA+/RF+ arthralgia patients and 30 HC from the Amsterdam Reade cohort. Quantitative PCR (qPCR) for B cell marker was performed of 45 ACPA+/RF+ arthralgia patients and six HC from the Amsterdam Reade cohort. Results The IFN-score (average of seven IFN-response genes) was measured at inclusion in an independent group of ACPA+/RF+ arthralgia patients at risk for RA (n=40). A total of 19 patients developed arthritis within a median period of 11 months (IQR 9–28). Comparative analysis of IFN-score high and low patients confirmed that the high IFN-score is associated with conversion to RA (p=0.025). In addition, the authors measured the IFN-score in PBMC from RA and preonset RA patients, and HC from the Northern Swedish Repository. Comparative analyses between the groups revealed that both preonset RA patients as well as RA patients had significantly increased IFN-scores compared to HC (Mann–Whitney U test p=0.0064 and p=0.0075, respectively). For the analysis of the role of B cells in development of RA the authors analysed the FACS profile of 87 ACPA+/RF+ at risk patients at inclusion, of who 22 developed RA within a median period to conversion of 10.5 months (IQR 4.5–13). The results confirmed that low B cell marker expression is significantly associated with RA conversion (p=0.01). An interim analysis with qPCR showed a trend towards the association between decreased B cell transcript marker and RA conversion (p=0.0714). Conclusion These results provide evidence for a role of IFN-activity and B cell abundance in the preclinical phase of RA. Further studies are aimed to demonstrate the diagnostic value of these markers.