Prevalence and validity of ACR/EULAR remission in four European early rheumatoid arthritis cohorts.

OBJECTIVES: In 2011 an ACR/EULAR collaboration developed new remission definitions for RA. In the present study, we evaluated the prevalence and predictive validity of these new ACR/EULAR remission criteria in 4 different European early rheumatoid arthritis cohorts. METHODS: Data from a tot al of 722 patients with early RA were analysed. Presence of remission at 6 months, as defined by one of the 4 proposed ACR/EULAR remission definitions was used to predict good functional and radiological outcome between 1 and 2 years of follow-up. RESULTS: Remission rates at 6 months ranged from 2-17% (Boolean definition) between the four cohorts. The level of HAQ and radiological damage varied between cohorts. Patients in remission at 6 months have an increased likelihood of long-term good outcome in terms of HAQ stability, but not radiographic stability. The performance of the practice definitions of remission was highly similar to the trial definitions. CRP status seems to add little information to the classification of remission in early RA. CONCLUSIONS: In clinical practice, a minority of patients with early RA achieves remission in the first 6 months of treatment. Remission at 6 months is predictive for good HAQ outcome between year 1 and 2 after inclusion, but not radiographic stability.

Low-avidity anticitrullinated protein antibodies (ACPA) are associated with a higher rate of joint destruction in rheumatoid arthritis.

OBJECTIVES: Anticitrullinated protein antibodies (ACPA) are specific for rheumatoid arthritis (RA) and have been implicated in disease pathogenesis. Previously we have shown that ACPA display a considerably lower avidity as compared with antibodies against recall antigens. Nonetheless, ACPA-avidity did vary between patients. As antibody mediated effects are influenced by antibody-avidity, we now investigated ACPA-avidity in relation to biological activity and clinical outcome. METHODS: We determined the avidity of ACPA and related this with severity of joint damage in two Dutch early-RA cohorts containing 199 and 132 patients respectively. Differences in effector functions of low- and high-avidity ACPA were studied. RESULTS: Extensive variation in ACPA-avidity between patients was observed. This allowed the analysis of the relationship between avidity and severity. The presence of low-avidity ACPA is associated with a higher rate of joint destruction. This finding was replicated in an independent cohort. Analysis of the properties of low-versus high-avidity ACPA revealed that low-avidity ACPA are less hampered in their ability to bind 'new' citrullinated antigens. Although no differences could be observed regarding cellular activation via Fc-γ receptors, low-avidity ACPA were more potent in activating the complement system. CONCLUSIONS: Patients with low-avidity ACPA display a higher rate of joint destruction. Low-avidity ACPA display a higher potency to interact with more citrullinated antigens in time and show that low-avidity ACPA are more potent in complement activation. These data indicate that (low) avidity impacts on the biological activity of ACPA and associates with a worse radiological outcome.

Risk of rheumatoid arthritis development in patients with unclassified arthritis according to the 2010 ACR/EULAR criteria for rheumatoid arthritis.

OBJECTIVE: Early recognition and treatment of RA is associated with an improved outcome. The 2010 ACR/EULAR criteria for RA identify RA patients earlier than the 1987 ACR criteria. Nevertheless, we recently observed that 24% of the 2010 unclassified arthritis (UA) patients develop RA during follow-up. Here we studied this frequency in other cohorts and evaluated the prognostic accuracy of ACPA and the Leiden prediction rule in 2010 UA patients. METHODS: The 2010 UA patients from three Early Arthritis Clinics were studied: 776 from Leiden, 121 from Birmingham and 322 from Amsterdam. Fulfilment of the 1987 ACR criteria during follow-up was studied as the primary outcome. DMARD prescription during the year and having a persistent course of arthritis over 7 years were studied as secondary outcomes in one cohort. The presence of ACPA and the prediction score at baseline were evaluated in relation to these outcomes. RESULTS: In the three cohorts, 24%, 26% and 12%, respectively, of the 2010 UA patients fulfilled the 1987 criteria after 1 year. However, some of these patients already fulfilled the 1987 criteria at baseline. In 1987 and 2010 UA patients, 15%, 21% and 9%, respectively, developed RA (1987) at 1 year. In these patients, 0-6% of the patients were ACPA positive and 0-1% had high prediction scores. Consequently a large majority of the UA patients with an unfavourable outcome was not recognized by these prognostic tools. CONCLUSION: A proportion of 2010 UA patients progress to RA. ACPA and the Leiden prediction rule are not useful in identifying these patients. These results imply that other predictive markers should be developed for 2010 UA patients.

Remission in early rheumatoid arthritis defined by 28 joint counts: limited consequences of residual disease activity in the forefeet on outcome.

UNLABELLED: Introduction The new American College for Rheumatology (ACR)/European League Against Rheumatism (EULAR) remission criteria are based on the assessment of 28 joints. A study was undertaken to study the consequences of remission misclassification due to residual disease activity in the feet on physical function and joint damage in the subsequent year in an observational early disease cohort. METHODS: All patients with rheumatoid arthritis at inclusion or at 1-year follow-up in the early arthritis cohort of the Jan van Breemen Institute, The Netherlands were included. ACR/EULAR remission definitions for trials and clinical practice were calculated twice, once using a 28-joint count and once using a 38-joint count that included the 10 metatarsophalangeal joints. Disease stability was defined as stable x-ray scores over 1 year (change ≤ 0 in Sharp/van der Heijde scores) and stable and low scores on the Health Assessment Questionnaire (HAQ change ≤ 0 and HAQ score consistently ≤ 0.5), all during the second year after inclusion. Analyses comprised residual disease activity (swollen or tender joints >0) in the feet of patients who fulfilled the candidate remission criteria using a 28-joint count and likelihood ratios of remission definitions to predict disease stability. RESULTS: Of 421 patients, 9-15% reached remission at 1 year using a 28-joint count. Of these, 26-40% showed activity in the feet. Misclassification due to reduced joint counts was observed in 2-3%. A state of remission increased the likelihood of stability of both x-ray and HAQ, with similar likelihood ratios for definitions using 38-joint counts and those using 28-joint counts. CONCLUSION: The ability of remission definitions with 28-joint counts versus 38-joint counts to predict long-term good radiological and functional outcome is similar. This confirms that inclusion of ankles and forefeet in the assessment of remission is not required, although inclusion of these joints in the examination is recommended.

Validation of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis: slight improvement over the 1987 ACR criteria.

BACKGROUND: Recently, an American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) collaboration developed new classification criteria for rheumatoid arthritis (RA). OBJECTIVE: To evaluate the diagnostic and discriminative ability of these new criteria compared with the 1987 ACR criteria and the Visser decision rule. METHODS: 455 patients with early arthritis were studied. The diagnostic performance of the criteria was evaluated using methotrexate treatment within 1 year, expert opinion RA and erosive disease as 'gold standards'. Erosive disease was defined as a 0-3 year change in radiographic score of ≥5. RESULTS: The discriminative ability of the three criteria sets (2010 ACR/EULAR, 1987 ACR criteria and Visser algorithm) was similar with areas under the curve of 0.71-0.78 ('gold standard' methotrexate), 0.74-0.80 (gold standard expert opinion RA) and 0.63-0.67 (gold standard erosive disease after 3 years). The sensitivity of the 2010 ACR/EULAR criteria was highest with 0.85 (gold standard methotrexate). 86% of patients with RA and 51% of 'non-RA' patients according to the new criteria used methotrexate. CONCLUSION: The 2010 ACR/EULAR criteria were slightly more sensitive, but otherwise performed similarly to the older criteria. A high percentage of 'non-RA' patients used methotrexate, the gold standard for RA. The ability of the new criteria to identify patients with erosive disease was low, possibly owing to the effect of intensive treatment.

Prevalence, Course, and Associated Factors of Pain in the Temporomandibular Joint in Early Rheumatoid Arthritis: Results of a Longitudinal Cohort Study.

AIMS: To assess the prevalence, 3-year course, and associated factors of temporomandibular joint (TMJ) pain in patients with newly diagnosed rheumatoid arthritis (RA). METHODS: A total of 264 patients with newly diagnosed RA were included. Patients were assessed after 3 months, 6 months, 9 months, 1 year, 1.5 years, 2 years, and 3 years. TMJ pain was scored by manual palpation, and the prevalence of TMJ pain was calculated at baseline and at all seven follow-up intervals during 3 years. Factors assessed for a potential association with TMJ pain at baseline included: demographic factors (gender and age), disease-related factors (symptom duration, rheumatoid factor [RF], anti-cyclic citrullinated protein [anti-CCP], C-reactive protein [CRP], and Disease Activity Score 28 [DAS28]), and functional factors (Health Assessment Questionnaire [HAQ] and European Quality of Life 5 Dimensions Questionnaire [EQ5D]-anxiety/depression). A stepwise logistic regression model was used to determine factors associated with TMJ pain in patients with RA. RESULTS: The prevalence of TMJ pain in patients with RA was 10.6% at baseline, which decreased to 3.6% in the first year after inclusion and remained stable thereafter. Disease activity as determined by the DAS28 was significantly associated with TMJ pain (odds ratio [OR] = 1.51; 95% confidence interval [95% CI] = 1.12-2.05; P = .009) at baseline. A second logistic regression analysis was performed with the following variables of the DAS28: erythrocyte sedimentation rate (ESR), tender joint count, swollen joint count, and global health. Tender joint count (OR = 1.06; 95% CI = 1.01-1.12; P = .03) and global health (OR = 1.02; 95% CI = 1.00-1.03; P = .03) were significantly associated with TMJ pain at baseline. The remaining factors included in the analysis were not significantly associated with TMJ pain at baseline. CONCLUSION: The prevalence of TMJ pain in patients with newly diagnosed RA is approximately 10% and decreases during follow-up, especially in the first year. Disease activity is a risk factor for TMJ pain in patients with newly diagnosed RA.

Detection of subclinical synovitis with macrophage targeting and positron emission tomography in patients with rheumatoid arthritis without clinical arthritis.

OBJECTIVE: To determine whether macrophage targeting by (R)-11C-PK11195 positron emission tomography (PET) can visualize subclinical joint inflammation in patients with rheumatoid arthritis (RA) without clinical arthritis during or after treatment, with flare as clinical outcome measure. METHODS: (R)-11C-PK11195 PET and contrast-enhanced magnetic resonance imaging (MRI) of hands/wrists were performed in 29 patients with RA without clinical arthritis. (R)-11C-PK11195 PET uptake (semiquantitative score 0-3) in metacarpophalangeal, proximal interphalangeal, and wrist joints (i.e., 22 joints per patient) was scored and summed to obtain a cumulative PET score (range 0-66). Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) was performed on similar joints. Synovitis and bone marrow edema scores (>1) were summed to obtain a cumulative MRI score (range 0-288). Occurrence of flare was determined during 3-year followup. RESULTS: Flare was observed in 17/29 patients (59%). (R)-11C-PK11195 PET showed enhanced tracer uptake in 16/29 patients (55%), of which 11 (69%) developed a flare. Highest cumulative PET scores (>6, n=3) corresponded with highest cumulative MRI scores (>39) and were related to development of flare in hands/wrists within 6 months. Cumulative PET scores of patients developing a flare were higher than those of patients without a flare [median (interquartile range) 2 (0-4.5) vs 0 (0-1), p<0.05]. In contrast, no significant differences were found between cumulative MRI scores of patients with and without a flare. CONCLUSION: (R)-11C-PK11195 PET showed enhanced uptake, pointing to presence of subclinical synovitis in over half of patients without clinical arthritis. (R)-11C-PK11195 PET may be of value for prediction of exacerbation of RA, since cumulative PET scores > 1 were associated with development of flare within 3 years.

Serum 14-3-3η is a novel marker that complements current serological measurements to enhance detection of patients with rheumatoid arthritis.

OBJECTIVE: Serum 14-3-3η is a novel joint-derived proinflammatory mediator implicated in the pathogenesis of rheumatoid arthritis (RA). In our study, we assessed the diagnostic utility of 14-3-3η and its association with standard clinical and serological measures. METHODS: A quantitative ELISA was used to assess 14-3-3η levels. Early (n=99) and established patients with RA (n=135) were compared to all controls (n=385), including healthy subjects (n=189). The sensitivity, specificity, positive and negative predictive values of 14-3-3η, and the likelihood ratios (LR) for RA were determined through receiver-operator curve analysis. The incremental value of adding 14-3-3η to anticitrullinated protein antibody (ACPA) and rheumatoid factor (RF) in diagnosing early and established RA was assessed. RESULTS: Serum 14-3-3η differentiated established patients with RA from healthy individuals and all controls (p<0.0001). A serum 14-3-3η cutoff of ≥0.19 ng/ml delivered a sensitivity and specificity of 77% and 93%, respectively, with corresponding LR positivity of 10.4. At this cutoff in early RA, 64% of patients with early RA were positive for 14-3-3η, with a corresponding specificity of 93% (LR+ of 8.6), while 59% and 57% were positive for ACPA or RF, respectively. When ACPA, RF, and 14-3-3η positivity were used in combination, 77 of the 99 patients (78%) with early RA were positive for any 1 of the 3 markers. Serum 14-3-3η did not correlate with C-reactive protein, erythrocyte sedimentation rate, or Disease Activity Score, but patients who were 14-3-3η-positive had significantly worse disease. CONCLUSION: Serum 14-3-3η is a novel RA mechanistic marker that is highly specific, associated with worse disease, and complements current markers, enabling a more accurate diagnosis of RA.

Foot-related health care use in patients with rheumatoid arthritis in an outpatient secondary care center for rheumatology and rehabilitation in The Netherlands: a cohort study with a maximum of fifteen years of followup.

OBJECTIVE: To describe foot-related health care use over time in a cohort of rheumatoid arthritis (RA) patients in an outpatient secondary care center for rheumatology and rehabilitation in The Netherlands. METHODS: A total of 1,087 patients with recent-onset RA from 1995 to September 2010 were included in the study. All foot-related visits to the podiatrist, rehabilitation physician, orthopedic surgeon, and the multidisciplinary foot-care clinic were registered and described. Logistic regression techniques for longitudinal data were used to analyze the course of foot-related health care use. RESULTS: A total of 32.9% of patients visited a podiatrist in secondary care during the course of their disease. For most patients, a visit to the podiatrist took place during the first year after diagnosis. This was followed by a significant decrease in visits in the ensuing years. Nine percent of patients visited the rehabilitation physician with foot symptoms, with peak prevalences between year 10 and 11 and during year 14 of followup. The orthopedic surgeon was visited by 5.3% of patients with foot symptoms, with a significant increase in visits over time. The multidisciplinary foot-care clinic was visited by 7.5% of patients. This was significantly associated with visits to the rehabilitation physician. CONCLUSION: In an outpatient secondary care center in The Netherlands, RA patients with foot symptoms visited the podiatrist in an early stage of the disease. When foot symptoms worsened, patients visited the rehabilitation physician, who subsequently referred patients to the multidisciplinary foot-care clinic for therapeutic footwear. The orthopedic surgeon was the final step in the management of foot symptoms.