M.D. Mjaavatten

Multinational evidence-based recommendations on how to investigate and follow-up undifferentiated peripheral inflammatory arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative

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.

Pattern of Joint Involvement and Other Disease Characteristics in 634 Patients with Arthritis of Less Than 16 Weeks’ Duration

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.

The likelihood of persistent arthritis increases with the level of anti-citrullinated peptide antibody and immunoglobulin M rheumatoid factor: a longitudinal study of 376 patients with very early undifferentiated arthritis

IntroductionWe 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.MethodsPatients 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.ResultsA 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.ConclusionsThe 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.

Should Anti-citrullinated Protein Antibody and Rheumatoid Factor Status Be Reassessed During the First Year of Followup in Recent-Onset Arthritis? A Longitudinal Study

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.

Development of a multimorbidity index: Impact on quality of life using a rheumatoid arthritis cohort.

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 patients overall well-being.

Early rheumatoid arthritis: The performance of the 2010 ACR/EULAR criteria for diagnosing RA

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.

Inconsistent Treatment with Disease-modifying Antirheumatic Drugs: A Longitudinal Data Analysis

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.

Algorithm for identification of undifferentiated peripheral inflammatory arthritis : a multinational collaboration through the 3e initiative.

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.

Role of erosions typical of rheumatoid arthritis in the 2010 ACR/EULAR rheumatoid arthritis classification criteria: results from a very early arthritis cohort

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.

Do rheumatologists know best? An outcomes study of inconsistent users of disease-modifying anti-rheumatic drugs

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.