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Extracellular vesicles (EVs) are implicated in the pathogenesis of rheumatoid arthritis (RA) but little is known about the composition of specific small EV (sEV) subpopulations. This study aimed to characterize the CD63, CD81 and CD9 tetraspanin profile in the membrane of single EVs in plasma from treatment naïve RA patients and assess potential discrepancies between methotrexate (MTX) responder groups. EVs isolated from plasma were characterized using transmission electron microscopy, and detection of surface markers (CD63, CD81 and CD9) on single EVs was performed on the ExoView platform. All RA patients (N = 8) were newly diagnosed, treatment naïve, females, ACPA positive and former smokers. The controls (N = 5) were matched for age and gender. After three months of MTX treatment, responders (N = 4) were defined as those with ΔDAS28 > 1.2 and DAS28 ≤ 3.2 post-treatment. The isolated EVs were 50-200 nm in size. The RA patients had a higher proportion of both CD9 and CD81 single positive sEVs compared to healthy controls, while there was a decrease in CD81/CD9 double positive sEVs in patients. Stratification of RA patients into MTX responders and non-responders revealed a distinctly higher proportion of CD81 single positive sEVs in the responder group. The proportion of CD81/CD9 double positive sEVs (anti-CD9 captured) was lower in the non-responders, but increased upon 3 months of MTX treatment. Our exploratory study revealed distinct tetraspanin profiles in RA patients suggesting their implication in RA pathophysiology and MTX treatment response., (© 2023. The Author(s).)

Background: Observational data are increasingly being used to conduct external comparisons to clinical trials. In this study, we empirically examined whether different methodological approaches to longitudinal missing data affected study conclusions in this setting., Methods: We used data from one clinical trial and one prospective observational study, both Norwegian multicenter studies including patients with recently diagnosed rheumatoid arthritis and implementing similar treatment strategies, but with different stringency. A binary disease remission status was defined at 6, 12, and 24 months in both studies. After identifying patterns of longitudinal missing outcome data, we evaluated the following five approaches to handle missingness: analyses of patients with complete follow-up data, multiple imputation (MI), inverse probability of censoring weighting (IPCW), and two combinations of MI and IPCW., Results: We found a complex non-monotone missing data pattern in the observational study (N = 328), while missing data in the trial (N = 188) was monotone due to drop-out. In the observational study, only 39.0% of patients had complete outcome data, compared to 89.9% in the trial. All approaches to missing data indicated favorable outcomes of the treatment strategy in the trial and resulted in similar study conclusions. Variations in results across approaches were mainly due to variations in estimated outcomes for the observational data., Conclusions: Five different approaches to handle longitudinal missing data resulted in similar conclusions in our example. However, the extent and complexity of missing observational data affected estimated comparative outcomes across approaches, highlighting the need for careful consideration of methods to account for missingness in this setting. Based on this empirical examination, we recommend using a prespecified advanced missing data approach to account for longitudinal missing data, and to conduct alternative approaches in sensitivity analyses., (© 2022. The Author(s).)

Background: Methotrexate (MTX) is the first line treatment of rheumatoid arthritis (RA), and methylation changes in bulk T cells have been reported after treatment with MTX. We have investigated cell-type specific DNA methylation changes across the genome in naïve and memory CD4 + T cells before and after MTX treatment of RA patients. DNA methylation profiles of newly diagnosed RA patients (N=9) were assessed by reduced representation bisulfite sequencing., Results: We found that MTX treatment significantly influenced DNA methylation levels at multiple CpG sites in both cell populations. Interestingly, we identified differentially methylated sites annotated to two genes; TRIM15 and SORC2 , previously reported to predict treatment outcome in RA patients when measured in bulk T cells. Furthermore, several of the genes, including STAT3 , annotated to the significant CpG sites are relevant for RA susceptibility or the action of MTX., Conclusion: We detected CpG sites that were associated with MTX treatment in CD4 + naïve and memory T cells isolated from RA patients. Several of these sites overlap genetic regions previously associated with RA risk and MTX treatment outcome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Guderud, Sunde, Flåm, Mæhlen, Mjaavatten, Norli, Evenrød, Andreassen, Franzenburg, Franke, Rayner, Gervin and Lie.)

The aim of the study was to  assess RF cross-reactivity to animal antibodies used in immunoassays, and to test if selected commercial immunoassays are vulnerable to interference from RF, causing false test results. Our study included samples from patients with RF-positive rheumatoid arthritis (RA) and controls (patients with RF-negative RA and psoriatic arthritis), included in an early arthritis-cohort. Reactivity to mouse IgG1, mouse IgG2a, rabbit IgG, bovine IgG, sheep/goat IgG and human IgG was analysed using in-house interference assays. RF-positive sera with strong reactivity to mouse IgG1 were analysed in three commercial immunoassays. To reveal interference, results before and after addition of blocking aggregated murine IgG1 were compared. Samples from 124 RF-positive RA patients and 66 controls were tested. We found considerably stronger reactivity toward animal antibodies, particularly mouse IgG1 (73% vs. 12%) and rabbit IgG (81% vs. 6%), in sera from RF-positive RA-patients compared to controls (p < 0.001). After selecting samples for testing in commercial assays, interference was revealed in 6/30 sera in the Architect β-hCG assay, 7/10 sera in the 27-plex cytokine assays, and in 2/33 samples in the Elecsys Soluble Transferrin Receptor assay. Our study revealed considerable RF reactivity to animal antibodies used in immunoassays and RF was associated with falsely elevated results in immunoassays used in clinical care and research. Clinicians, laboratorians, researchers and assay manufacturers must be alert to the risk of falsely elevated test results in RF-positive RA patients., (© 2021. The Author(s).)

Rheumatoid arthritis (RA) is a complex disease with a wide range of underlying susceptibility factors. Recently, dysregulation of microRNAs (miRNAs) in RA have been reported in several immune cell types from blood. However, B cells have not been studied in detail yet. Given the autoimmune nature of RA with the presence of autoantibodies, CD19+ B cells are a key cell type in RA pathogenesis and alterations in CD19+ B cell subpopulations have been observed in patient blood. Therefore, we aimed to reveal the global miRNA repertoire and to analyze miRNA expression profile differences in homogenous RA patient phenotypes in blood-derived CD19+ B cells. Small RNA sequencing was performed on CD19+ B cells of newly diagnosed untreated RA patients (n=10), successfully methotrexate (MTX) treated RA patients in remission (MTX treated RA patients, n=18) and healthy controls (n=9). The majority of miRNAs was detected across all phenotypes. However, significant expression differences between MTX treated RA patients and controls were observed for 27 miRNAs, while no significant differences were seen between the newly diagnosed patients and controls. Several of the differentially expressed miRNAs were previously found to be dysregulated in RA including miR-223-3p, miR-486-3p and miR-23a-3p. MiRNA target enrichment analysis, using the differentially expressed miRNAs and miRNA-target interactions from miRTarBase as input, revealed enriched target genes known to play important roles in B cell activation, differentiation and B cell receptor signaling, such as STAT3 , PRDM1 and PTEN. Interestingly, many of those genes showed a high degree of correlated expression in CD19+ B cells in contrast to other immune cell types. Our results suggest important regulatory functions of miRNAs in blood-derived CD19+ B cells of MTX treated RA patients and motivate for future studies investigating the interactive mechanisms between miRNA and gene targets, as well as the possible predictive power of miRNAs for RA treatment response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Heinicke, Zhong, Flåm, Breidenbach, Leithaug, Mæhlen, Lillegraven, Aga, Norli, Mjaavatten, Haavardsholm, Zucknick, Rayner and Lie.)

Objective: The present study was undertaken to investigate the joint distribution and 2-year outcome of patients with recent-onset monoarthritis., Methods: Adult patients with clinically apparent monoarthritis of ≤16 weeks' duration were included in a multicenter 2-year longitudinal study. Clinical characteristics, joint distribution, development of chronic inflammatory rheumatic disease (CIRD), as well as classification criteria according to the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 criteria for RA were studied. Predictors for development of CIRD were analyzed by multivariable logistic regression analyses., Results: The knee (49.3%), ankle (16.7%), and wrist (14.1%) were the most frequently affected joints among the 347 included patients. A total of 91 patients (26.2%) developed CIRD during follow-up; 21 (6.1%) were diagnosed with RA, and 16 (4.6%) with psoriatic arthritis. Longer duration of joint swelling, joint localization, and anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF) positivity were independent predictors of CIRD. Six of 58 patients (10.3%) with ankle monoarthritis and 21 of 49 patients (42.9%) with wrist monoarthritis developed CIRD during follow-up. The 2010 ACR/EULAR Criteria for RA identified all patients diagnosed with seropositive RA at an early stage, mostly within 3 months., Conclusion: Approximately one-fourth of patients with recent-onset monoarthritis developed CIRD over 2 years. Patients presenting with ankle arthritis rarely developed CIRD, whereas patients presenting with wrist arthritis more frequently did so. Longer duration of joint swelling and ACPA and RF positivity were also predictive of CIRD. Our findings facilitate the early identification of patients with monoarthritis who have an unfavorable prognosis., (© 2017, American College of Rheumatology.)

Objective: To compare achievement of remission in two early rheumatoid arthritis (RA) treat-to-target (TTT) cohorts, one tight control cohort targeting stringent remission in a randomized controlled strategy trial and one observational cohort targeting a looser definition of remission in clinical practice., Methods: We analyzed data from the ARCTIC trial and the NOR-VEAC observational study. Both were Norwegian multicenter studies including disease modifying anti-rheumatic drug (DMARD)-naïve RA-patients and implementing TTT. The target in ARCTIC was remission defined as a Disease Activity Score (DAS44) <1.6 plus 0 of 44 swollen joint count, while the target in NOR-VEAC was the less stringent remission of DAS28<2.6. We assessed achievement of the study-specific targets and compared achievement of the ACR/ EULAR Boolean remission during two years of follow-up., Results: We included 189 patients from ARCTIC and 330 patients from NOR-VEAC. More than half in each cohort had reached the study-specific target at 6 months, increasing to more than 60% at 12 and 24 months. The odds of reaching ACR/EULAR Boolean remission during follow-up were higher in ARCTIC than in NOR-VEAC, with statistically significant differences at 3 months (OR 1.73; 95% CI 1.03-2.89), 12 months (OR 1.97; 95% CI 1.21-3.20) and 24 months (OR 1.82; 95% CI 1.05 - 3.16)., Conclusion: A majority of patients in both cohorts reached the study-specific treatment targets. More patients in ARCTIC than in NOR-VEAC achieved ACR/EULAR Boolean remission during follow-up, suggesting that targeting a more stringent definition of remission provide further potential for favorable outcomes of a TTT strategy., (This article is protected by copyright. All rights reserved.)

Background: Differences in DNA methylation have been reported in B and T lymphocyte populations, including CD4 + T cells, isolated from rheumatoid arthritis (RA) patients when compared to healthy controls. CD4 + T cells are a heterogeneous cell type with subpopulations displaying distinct DNA methylation patterns. In this study, we investigated DNA methylation using reduced representation bisulfite sequencing in two CD4 + T cell populations (CD4 + memory and naïve cells) in three groups: newly diagnosed, disease modifying antirheumatic drugs (DMARD) naïve RA patients ( N = 11), methotrexate (MTX) treated RA patients ( N = 18), and healthy controls ( N = 9) matched for age, gender and smoking status. Results: Analyses of these data revealed significantly more differentially methylated positions (DMPs) in CD4 + memory than in CD4 + naïve T cells (904 vs. 19 DMPs) in RA patients compared to controls. The majority of DMPs (72%) identified in newly diagnosed and DMARD naïve RA patients with active disease showed increased DNA methylation (39 DMPs), whereas most DMPs (80%) identified in the MTX treated RA patients in remission displayed decreased DNA methylation (694 DMPs). Interestingly, we also found that about one third of the 101 known RA risk loci overlapped (±500 kb) with the DMPs. Notably, introns of the UBASH3A gene harbor both the lead RA risk SNP and two DMPs in CD4 + memory T cells. Conclusion: Our results suggest that RA associated DNA methylation differences vary between the two T cell subsets, but are also influenced by RA characteristics such as disease activity, disease duration and/or MTX treatment., (Copyright © 2020 Guderud, Sunde, Flåm, Mæhlen, Mjaavatten, Lillegraven, Aga, Evenrød, Norli, Andreassen, Franzenburg, Franke, Haavardsholm, Rayner, Gervin and Lie.)

Objective: To assess the 2-year effect on disease activity and health-related quality of life (HRQoL) of implementing a clinical practice treat-to-target (T2T) strategy in patients with rheumatoid arthritis (RA)., Methods: Patients in the Norwegian Very Early Arthritis Cohort 2.0 (NOR-VEAC 2.0), included 2010-2015, were treated according to T2T principles with visits at baseline, 3, 6, 9, 12 months, then every 6 months plus monthly visits until DAS28 <2.6. These patients were compared to a pre-T2T cohort of patients included in the Norwegian Disease Modifying Anti-Rheumatic Drug (NOR-DMARD) register 2006-2009. Both groups had a clinical diagnosis of RA (≤1 year) and were DMARD naïve. Disease activity and HRQoL outcomes were analysed, and the primary outcome was SDAI remission (≤3.3) at 2years., Results: The T2T cohort included 293 patients (mean (SD) age 54 (13) years, 66% females, disease duration median (25,75 perc) 98 (57,164) days) and the routine care cohort 392 patients (age 54 (13) years, 68% females, 4 (0,30) days since diagnosis). At 2years, the proportion of patients achieving SDAI remission was 46% in the T2T cohort compared to 31% in the routine care cohort. EQ-5D was similar at baseline, but differed significantly between groups at 2years (median (25,75 perc) 0.77 (0.69, 0.85) vs 0.73 (0.59, 0.80), p < 0.001). Methotrexate monotherapy was the dominant DMARD regimen used to achieve SDAI remission in both cohorts., Conclusion: Higher remission rates and better HRQoL were achieved in patients following a T2T strategy in clinical practice compared to routine care., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: To describe the diagnostic spectrum, arthritis persistency and clinical outcomes after 2 years in patients with inflammatory arthritis (IA) of less than 16 weeks' duration., Methods: Data from the Norwegian Very Early Arthritis Clinic, a 2-year longitudinal observational study of adults with IA of ≤16 weeks' duration, were used. Exclusion criteria were arthritis due to crystal deposits, trauma, osteoarthritis and septic arthritis. In all patients who had any follow-up information (population A), clinical diagnoses and persistency of arthritis were described. For patients with 2-year follow-up (population B), we also studied other clinical outcomes (disease activity, pain, fatigue, functional disability and health-related quality of life)., Results: In population A (n=1017) median (25th-75th percentile) duration of joint swelling was 35.0 (13.0-66.5) days, mean (SD) age 45.7 (14.8) years, 55.2% were females and 17.8% anticitrullinated protein antibodies positive. The most common final diagnoses were undifferentiated arthritis (UA) (41.7%), rheumatoid arthritis (RA) (24.1%) and reactive arthritis (18.1%). After 2 years, the arthritis had resolved in 59% of the patients. The remaining 41.0% had persistent disease defined by disease modifying antirheumatic drug (DMARD) use (32.1%) or persistent joint swelling without DMARD use (8.9%). In population B (n=669), all clinical outcomes improved significantly (P<0.001). Baseline joint pain and fatigue were similar across diagnoses., Conclusions: Among 1017 patients with IA of ≤16 weeks' duration, UA was the most common diagnosis after 2 years, and less than one-fourth were diagnosed with RA. Arthritis resolved without DMARDs in the majority of the patients. All clinical parameters improved significantly over a 2-year course., Competing Interests: Competing interests: TKK has received fees for speaking and/or consulting from AbbVie, Biogen, BMS, Boehringer Ingelheim, Celltrion, Eli Lilly, Epirus, Janssen, Merck-Serono, MSD, Mundipharma, Novartis, Oktal, Orion Pharma, Hospira/Pfizer, Roche, Sandoz and UCB.

Objective: To determine how the European League Against Rheumatism (EULAR) definition of erosive disease (erosion criterion) contributes to the number of patients classified as rheumatoid arthritis (RA) according to the 2010 American College of Rheumatology/EULAR RA classification criteria (2010 RA criteria) in an early arthritis cohort., Methods: Patients from the observational study Norwegian Very Early Arthritis Clinic with joint swelling ≤16 weeks, a clinical diagnosis of RA or undifferentiated arthritis, and radiographs of hands and feet were included. Erosive disease was defined according to the EULAR definition accompanying the 2010 RA criteria. We calculated the additional number of patients being classified as RA based on the erosion criteria at baseline and during follow-up., Results: Of the 289 included patients, 120 (41.5%) fulfilled the 2010 RA criteria, whereas 15 (5.2%) fulfilled only the erosion criterion at baseline. 118 patients had radiographic follow-up at 2 years, of whom 6.8% fulfilled the 2010 RA criteria and only one patient fulfilled solely the erosion criterion during follow-up., Conclusion: Few patients with early arthritis were classified as RA based on solely the erosion criteria, and of those who did almost all did so at baseline., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To examine the 2-year disease course in patients with undifferentiated arthritis (UA) focusing on fulfillment of the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) rheumatoid arthritis (RA) classification criteria., Methods: Data were provided by the Norwegian Very Early Arthritis Clinic study, which included patients presenting with ≥ 1 swollen joint of ≤ 16 weeks' duration. UA was defined as patients not fulfilling the 2010 ACR/EULAR RA criteria and who did not have a clinical diagnosis other than RA at baseline. The main outcome was fulfillment of the 2010 RA criteria. Secondary outcomes were disease-modifying antirheumatic drug (DMARD) use, resolution of synovitis without use of DMARD during followup, and final clinical diagnosis., Results: We included 477 patients with UA of whom 47 fulfilled the 2010 ACR/EULAR RA criteria during followup (UA-RA) and 430 did not (UA-non-RA). Of the UA-RA patients, 70% fulfilled the criteria within the first 6 months. UA-RA patients were older, more often positive for rheumatoid factor and anticitrullinated protein antibodies, female, and ever smokers, and they more often presented with polyarticular arthritis, small joint involvement, and a swollen shoulder joint. During followup, 53% of UA-RA patients vs 13% of UA-non-RA patients used DMARD (p < 0.001). Overall, 71% of patients with UA achieved absence of clinical synovitis at final followup without use of DMARD. The most frequent final clinical diagnosis was UA (61%)., Conclusion: Only 9.8% of patients with UA fulfilled the 2010 RA criteria during 2-year followup. Small joint involvement and swollen shoulder joint were among the factors associated with RA development. In two-thirds of patients with UA, the arthritis resolved without use of DMARD.

Objectives: To study occurrence of and factors associated with self-limiting arthritis among patients fulfilling the 2010 ACR/EULAR classification criteria for rheumatoid arthritis (RA) (2010 RA criteria) in patients with ≤16 weeks׳ duration of joint swelling., Methods: We applied the 2010 RA criteria in 1118 patients included in a 2-year longitudinal cohort. In all, 256 patients fulfilled the 2010 RA criteria at baseline; outcome was defined as either "self-limiting arthritis" (no DMARD use during follow-up, no swollen joints at last assessment, and no final clinical diagnosis of RA) or "persistent disease." The associations between baseline characteristics, including the components of the 2010 RA criteria score, and outcomes were studied., Results: In total, 36 of 256 patients (14.1%) classified as having RA had self-limiting arthritis. These patients differed from patients with persistent disease according to ACPA positivity (11.1% vs. 65.0%, p < 0.001), duration of joint swelling (median = 47.5 vs. 66.0 days, p = 0.002), 2010 RA criteria points (median = 6.0 vs. 7.0, p < 0.001), and ever smoking (52.8% vs. 74.5%, p = 0.01). Having no serology points and no duration points were independent predictors of self-limiting arthritis. The rate of self-limiting arthritis was 2.7% vs. 29.4% among ACPA positive vs. ACPA negative patients (p < 0.001), and 32.5% when duration of joint swelling was <4 weeks vs. 10.6% with longer duration (p < 0.001)., Conclusions: Negative ACPA status, short duration of joint swelling and being a never smoker were factors associated with self-limiting arthritis in early arthritis patients classified as having RA at presentation. Our findings contribute to identify patients who potentially do not need DMARDs and who should not be included in early RA clinical drug trials., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: We conducted a longitudinal observational study of biological disease-modifying antirheumatic drugs (bDMARD) to describe the proportions of patients with rheumatoid arthritis in remission who discontinued these agents, and to assess the potential predictors of the decision to discontinue., Methods: We used data from the US COnsortium of Rheumatology Researchers Of North America (CORRONA) and the Japanese National Database of Rheumatic Diseases by iR-net in Japan (NinJa) registries, and ran parallel analyses. Patients treated with bDMARD who experienced remission (defined by the Clinical Disease Activity Index ≤ 2.8) were included. The outcome of interest was the occurrence of bDMARD discontinuation while in remission. The predictors of discontinuation were assessed in the Cox regression models. Frailty models were also used to examine the effects of individual physicians in the discontinuation decision., Results: The numbers of eligible patients who were initially in remission were 6263 in the CORRONA and 744 in the NinJa. Among these patients, 10.0% of patients in CORRONA and 11.8% of patients in NinJa discontinued bDMARD while in remission over 5 years, whereas many of the remaining patients lost remission before discontinuing bDMARD. Shorter disease duration was associated with higher rates of discontinuation in both cohorts. In CORRONA, methotrexate use and lower disease activity were also associated with discontinuation. In frailty models, physician random effects were significant in both cohorts., Conclusion: Among patients who initially experienced remission while receiving bDMARD, around 10% remained in remission and then discontinued bDMARD in both registries. Several factors were associated with more frequent discontinuation while in remission. Physician preference likely is also an important correlate of bDMARD discontinuation, indicating the need for standardization of practice.

Objective: To develop a multimorbidity index (MMI) based on health-related quality of life (HRQol)., Methods: The index was developed in an observational RA cohort. In all, 40 morbidities recommended as core were identified using ICD-9 codes. MMIs of two types were calculated: one by enumerating morbidities (MMI.count) and the other by weighting morbidities based on their association with HRQol as assessed by EQ-5D in multiple linear regression analysis (using β-coefficients; MMI.weight). MMIs were compared to the Charlson comorbidity index (CCI) and externally validated in an international RA cohort (COMORA Study)., Results: In all, 544 out of 876 patients were multimorbid. MMI.count was in the range 1-16 (median = 2) and MMI.weight in the range 0-38 (median = 1). Both indices were more strongly associated with EQ-5D than CCI (Spearman: MMI.count = -0.20, MMI.weight = -0.26, and CCI = -0.10; p < 0.01). R(2) obtained by linear regression using EQ-5D as a dependent variable and various indices as independent variables, adjusted for age and gender, was the highest for MMI (R(2): MMI.count = 0.05, MMI.weight = 0.11, and CCI = 0.02). When accounting for clinical disease activity index (CDAI) R(2) increased: MMI.count = 0.18, MMI.weight = 0.22, and CCI = 0.17, still showing higher values of MMI compared with CCI. External validation in different RA cohorts (COMORA, n = 3864) showed good performance of both indices (linear regression including age, gender, and disease activity R(2) = 0.30 for both MMIs)., Conclusion: In our cohort, MMI based on EQ-5D performed better than did CCI. Findings were reproducible in another large RA cohort. Not much improvement was gained by weighting; therefore a simple counted index could be useful to control for the effect of multimorbidity on patient's overall well-being., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Current recommendations advocate treatment with disease-modifying anti-rheumatic drugs (DMARDs) in all patients with active rheumatoid arthritis (RA). We analyzed short-term disease outcome in patients according to the consistency of DMARD use in a clinical rheumatology cohort., Methods: Patients in an RA registry (n = 617) were studied for DMARD use at semi-annual study time points during the first 18 months of follow-up and were divided into 4 groups according to the number of study time points with any DMARD use [0-1 study time points (n = 31), 2 study time points (n = 24), 3 study time points (n = 77), and 4 study time points (n = 485)]. The primary outcome analyses were performed at 24 months and included Disease Activity Score 28 (DAS28-CRP), modified Health Assessment Questionnaire (MHAQ) change, Short Form Health Survey-12 physical and mental summary scores (SF-12 PCS, SF-12 MCS), EuroQol 5-Dimensional health index (EQ-5D), and radiographic progression. Unadjusted, adjusted, and analyses stratified for seropositivity and disease activity were performed. A secondary analysis investigated 36-month outcomes., Results: No significant 24-month outcome differences could be found between the DMARD use categories. For seropositive patients, there was evidence of a linear trend for SF-12 PCS (p = 0.02) and EQ-5D (p = 0.01) with worse outcomes for inconsistent DMARD users. At 36 months, there was a linear trend for higher DAS28-CRP scores for inconsistent users (p < 0.01)., Conclusions: Overall, we found poor correlation between inconsistent DMARD use and short-term disease outcome. However, outcome in the longer term could be negatively influenced by inconsistent DMARD use, as well as short-term outcome in seropositive patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Current recommendations advocate treatment with disease-modifying antirheumatic drugs (DMARD) in all patients with active rheumatoid arthritis (RA). We investigated the frequency of and reasons for inconsistent DMARD use among patients in a clinical rheumatology cohort., Methods: Patients in the Brigham Rheumatoid Arthritis Sequential Study were studied for DMARD use (any or none) at each semiannual study timepoint during the first 2 study years. Inconsistent use was defined as DMARD use at ≤ 40% of study timepoints. Characteristics were compared between inconsistent and consistent users (> 40%), and factors associated with inconsistent DMARD use were determined through multivariate logistic regression. A medical record review was performed to determine the reasons for inconsistent use., Results: Of 848 patients with ≥ 4 out of 5 visits recorded, 55 (6.5%) were inconsistent DMARD users. Higher age, longer disease duration, and rheumatoid factor negativity were statistically significant correlates of inconsistent use in the multivariate analyses. The primary reasons for inconsistent use identified through chart review, allowing for up to 2 co-primary reasons, were inactive disease (n = 28, 50.9%), intolerance to DMARD (n = 18, 32.7%), patient preference (n = 7, 12.7%), comorbidity (n = 6, 10.9%), DMARD not being effective (n = 3, 5.5%), and pregnancy (n = 3, 5.5%). During subsequent followup, 14/45 (31.1%) inconsistent users with sufficient data became consistent users of DMARD., Conclusion: A small proportion of patients with RA in a clinical rheumatology cohort were inconsistent DMARD users during the first 2 years of followup. While various patient factors correlate with inconsistent use, many patients re-start DMARD and become consistent users over time.

New classification criteria for rheumatoid arthritis (RA) were presented by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) in 2010, aiming for early identification of patients at risk of developing persistent and erosive arthritis. Since their publication, the criteria have been extensively validated against several reference standards, but there is still debate regarding how the criteria should be implemented in studies and clinical care. We present an overview of the published validation studies and discuss the strengths and limitations of the classification criteria, as well as whether the criteria are ready for diagnostic purposes in clinical practice., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: Presence and levels of antibodies contribute to the classification of rheumatoid arthritis. We investigated the longitudinal course of anti-citrullinated protein antibodies (ACPA) and immunoglobin M (IgM) rheumatoid factor (RF) during the first year after arthritis onset in patients with very short disease duration., Methods: Patients (aged 18-75 years) with ≥ 1 swollen joint of ≤ 16 weeks' duration had assessments of ACPA (2nd generation anti-cyclic citrullinated peptide antibodies, anti-CCP2) and IgM RF at inclusion and after 3, 6, and 12 months. Frequencies of seroconversions (negative to positive and vice versa) and changes in antibody levels during followup were determined., Results: A total of 281 early arthritis patients (median duration of joint swelling 32 days, 14.2% ACPA positives, 12.8% IgM RF positives) with 978 longitudinally collected serum samples were included. Only 5 patients (1.8%) negative for both antibodies at baseline turned antibody-positive during followup, while 9 antibody-positive patients (3.2%) turned antibody-negative. ACPA was more stable than RF regarding both status and levels., Conclusion: Antibody status (ACPA/RF) is a stable phenotype in very early arthritis, as seroconversion was only found in 5% of patients. Repeated measurement of ACPA or RF during the first year after onset of arthritis does not offer major additional information.

Objective: Recently, new classification criteria for rheumatoid arthritis (RA) have been devised by methodology that used first a quantitative approach (data from databases), then a qualitative approach (consensus; based on paper patients), and finally a common sense-based approach (evaluation of the former phases). Now the individual items that make up these criteria are being evaluated. This study was undertaken to analyze the item "autoantibodies," in particular rheumatoid factor (RF) level., Methods: Three separate cohorts comprising a total of 972 patients with undifferentiated arthritis were studied for RA development (according to the 1987 American College of Rheumatology criteria) and arthritis persistence. The positive predictive value (PPV), negative predictive value (NPV), and likelihood ratios (LRs) were compared between different levels of RF and the presence of anti-citrullinated protein antibody (ACPA). A similar comparison was made in 686 RA patients for the rate of joint destruction and achievement of sustained disease-modifying antirheumatic drug-free remission during 7 years of followup. The variation in RF levels obtained by different measurement methods in the same RF-positive sera was explored., Results: Compared to high RF levels, presence of ACPA had a better balance between positive LR and negative LR and between PPV and NPV for RA development. The additive value of ACPA assessment after testing for RF level was higher than vice versa. The association between high RF level and RA severity was not as strong as that between ACPA antibodies and RA severity. The RF level obtained by different methods in the same patients' sera varied considerably., Conclusion: Our findings indicate that determination of RF level is subject to large variation; high RF level has limited additive prognostic value compared to ACPA positivity. Thus, omitting RF level and using RF presence, ACPA presence, and ACPA level may improve the 2010 criteria for RA., (Copyright © 2011 by the American College of Rheumatology.)

Objective: To develop an algorithm for identification of undifferentiated peripheral inflammatory arthritis (UPIA)., Methods: An algorithm for identification of UPIA was developed by consensus during a roundtable meeting with an expert panel. It was informed by systematic reviews of the literature used to generate 10 recommendations for the investigation and followup of UPIA through the 3e initiative. The final recommendations from the 3e UPIA Initiative were made available to the panel to guide development of the algorithm. The algorithm drew on the clinical experience of the consensus panel and evidence from the literature where available., Results: In patients presenting with joint swelling a thorough evaluation is required prior to diagnosing UPIA. After excluding trauma, the differential diagnosis should be formulated based on history and physical examination. A minimum set of investigations is suggested for all patients, with additional ones dependent on the most probable differential diagnoses. The diagnosis of UPIA can be made if, following these evaluations, a more specific diagnosis is not reached. Once a diagnosis of UPIA is established, patients should be closely followed as they may progress to a specific diagnosis, remit, or persist as UPIA, and additional investigations may be required over time., Conclusion: Our algorithm presents a diagnostic approach to identifying UPIA in patients presenting with joint swelling, incorporating the dynamic nature of the condition with the potential to evolve over time.

Objective: To develop evidence-based recommendations on how to investigate and follow-up undifferentiated peripheral inflammatory arthritis (UPIA)., Methods: 697 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2008-9 consisting of three separate rounds of discussions and modified Delphi votes. In the first round 10 clinical questions were selected. A bibliographic team systematically searched Medline, Embase, the Cochrane Library and ACR/EULAR 2007-2008 meeting abstracts. Relevant articles were reviewed for quality assessment, data extraction and synthesis. In the second round each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed., Results: A total of 39,756 references were identified, of which 250 were systematically reviewed. Ten multinational key recommendations about the investigation and follow-up of UPIA were formulated. One recommendation addressed differential diagnosis and investigations prior to establishing the operational diagnosis of UPIA, seven recommendations related to the diagnostic and prognostic value of clinical and laboratory assessments in established UPIA (history and physical examination, acute phase reactants, autoantibodies, radiographs, MRI and ultrasound, genetic markers and synovial biopsy), one recommendation highlighted predictors of persistence (chronicity) and the final recommendation addressed monitoring of clinical disease activity in UPIA., Conclusions: Ten recommendations on how to investigate and follow-up UPIA in the clinical setting were developed. They are evidence-based and supported by a large panel of rheumatologists, thus enhancing their validity and practical use.

Introduction: We wanted to assess the importance of the levels of anti-citrullinated peptide antibody (anti-CCP) and immunoglobulin M (IgM) rheumatoid factor (RF) in predicting development of persistent arthritis from undifferentiated arthritis (UA), and to investigate whether there is an added predictive value for persistent arthritis in testing for both anti-CCP and IgM RF., Methods: Patients with UA (exclusion of definite non-rheumatoid arthritis (RA) diagnoses) included in the Norwegian very early arthritis clinic were assessed for development of persistent arthritic disease. The effect of antibody level on the likelihood of persistent arthritis was investigated, and the sensitivity and specificity for persistent arthritis for anti-CCP and IgM RF, separately and combined, was determined., Results: A total of 376 UA patients were included (median arthritis duration 32 days). 59 (15.7%) patients were IgM RF positive, and 62 (16.5%) anti-CCP positive. One hundred, seventy-four (46.3%) had persistent disease after one year. Overlap of anti-CCP and IgM RF positivity was 58%. Sensitivity/specificity for persistent arthritis was 28/95% for IgM RF alone, 30/95% for anti-CCP alone, and 37/92% for positivity of both anti-CCP and IgM RF. The likelihood for persistent disease increased with increasing levels of both anti-CCP and IgM RF., Conclusions: The likelihood of developing persistent arthritis in UA patients increases with the level of anti-CCP and IgM RF. Testing both anti-CCP and IgM RF has added predictive value in UA patients. This study suggests that antibody level should be taken into account when making risk assessments in patients with UA.

Objective: To investigate the distribution of joint involvement in a cohort of patients with very recent onset arthritis and describe the disease characteristics in these patients., Methods: A very early arthritis clinic (NOR-VEAC) was established as a multicenter study. General practitioners were asked to refer patients presenting with at least 1 swollen joint of maximum 16 weeks' duration. Clinical and laboratory markers were examined., Results: We included 634 patients during the first 3 years, with mean (25th-75th percentile) arthritis duration of 30 (11-63) days. Monoarthritis was present in 243 (38.3%) patients, 216 (34.1%) had oligoarthritis, and 175 (27.6%) polyarthritis. Patients with polyarthritis were older, had longer duration of arthritis, and were more frequently anti-cyclic citrullinated peptide antibody and rheumatoid factor-positive. Patients in all 3 joint pattern groups (mono-/oligo-/polyarthritis) reported substantial effect on physical function, pain, and fatigue and had elevated levels of acute-phase reactants. Knee or ankle arthritis was most frequent in patients with mono- and oligoarthritis, whereas small joint involvement was most frequent in patients with polyarthritis., Conclusion: Patients with recent-onset arthritis report a substantial influence on health status. Mono- and oligoarthritis are at least as frequent as polyarthritis. Polyarthritic patients more frequently exhibit features associated with a worse outcome.

Introduction: The current 1987 American College of Rheumatology (ACR) classification criteria for rheumatoid arthritis (RA) have proven less useful in early arthritis. The objective of this study was to identify and compare predictors of three relevant outcomes of chronic arthritis in a cohort of very early arthritis patients., Methods: The Norwegian Very Early Arthritis Cohort (NOR-VEAC) includes adult patients with at least one swollen joint of < or = 16 weeks' duration. Patients are followed for 2 years with comprehensive clinical and laboratory examinations. Logistic regression analyses were performed to determine independent predictors of three outcomes: persistent synovitis, prescription of disease-modifying anti-rheumatic drugs (DMARDs), and established clinical RA diagnosis within one year., Results: Of 384 patients eligible for one year follow-up (56.3% females, mean (SD) age 45.8 (14.7) years, median (IQR) duration of arthritis 31 (10-62) days), 14.4% were anti-CCP2 positive, and 11.2% were IgM RF positive. 98 patients (25.5%) had persistent synovitis, 106 (27.6%) had received DMARD treatment during follow-up, while 68 (17.7%) were diagnosed with RA. Consistent independent predictors across all three outcomes were positive anti-citrullinated protein antibody (ACPA) status (odds ratio (OR) 3.2, 5.6 and 19.3), respectively, and small joint arthritis (proximal interphalangeal joint (PIP), metacarpo-phalangeal joint (MCP), and/or metatarso-phalangeal joint (MTP) joint swelling) (OR 1.9, 3.5, and 3.5, respectively)., Conclusions: Positive ACPA status and small joint arthritis were consistent predictors of three relevant outcomes of chronic arthritis in very early arthritis patients. This consistency supports DMARD prescription as a valid surrogate endpoint for chronic arthritis. Importantly, this surrogate is used in ongoing efforts to develop new diagnostic criteria for early RA.