Predictive values of anti-cyclic citrullinated peptide antibodies and rheumatoid factor in relation to serological aspects of the ACR/EULAR 2010 classification criteria for rheumatoid arthritis.

Objective: In this retrospective population-based register study, we wanted to determine the positive predictive values (PPVs) of immunoglobulin M rheumatoid factor (IgM RF) and anti-citrullinated protein antibodies (ACPAs) at 3 × upper normal limit (UNL), since they are weighted equally in the American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) 2010 criteria for rheumatoid arthritis (RA).Methods: Test results, ordering unit, test date, and patient social security number were collected from the Department of Clinical Immunology at Odense University Hospital from 2007 to 2016 and merged with patient diagnosis from the Danish National Patient Registry.Results: The PPV of IgM RF at 3 × UNL was 14%, compared to a PPV of 43% for ACPAs at 3 × UNL.Conclusion: The PPV of ACPAs is higher than the PPV of IgM RF at 3 × UNL. These findings are not reflected in the ACR/EULAR 2010 classification criteria for RA.

Galectin-3 is Persistently Increased in Early Rheumatoid Arthritis (RA) and Associates with Anti-CCP Seropositivity and MRI Bone Lesions, While Early Fibrosis Markers Correlate with Disease Activity.

Galectin-3 has been suggested as a pro-inflammatory mediator in animal arthritis and rheumatoid arthritis (RA). We aimed to study the serum level of galectin-3 in patients with newly diagnosed RA and associations with disease profile, Magnetic resonance imaging (MRI) findings and seromarkers of synovial matrix inflammation. One hundred and sixty DMARD naïve patients newly diagnosed with RA were included (CIMESTRA study). Clinical, serological and imaging data were recorded before treatment and at 6 weeks, 3 and 12 months. Galectin-3 and hyaluronan (HYA) were measured by ELISA (R&D and Corgenix, USA), and the N-terminal propeptide of type III collagen (PIIINP) by radioimmunoassay (Orion Diagnostica, Finland). One hundred and nineteen, 87 and 60 blood donors served as controls for galectin-3, HYA and PIIINP, respectively. Baseline galectin-3 was significantly elevated in anti-CCP positive (4.2 µg/l IQR [3.6;6.1]) patients as compared with anti-CCP negatives (4.0 µg/l [2.6;4.9], P = 0.05) and controls (3.8 µg/l [3.0;4.8], P < 0.01). During treatment, galectin-3 remained elevated, but increased transiently with peak values at 6 weeks. Galectin-3 correlated with baseline smoking, anti-CCP, and with MRI erosion score after 1 year of follow-up. HYA and PIIINP were elevated (P < 0.001) irrespective of anti-CCP status and correlated positively with synovitis assessed clinically and by MRI. HYA and PIIINP did not correlate with galectin-3. These observations indicate that HYA and PIIINP mainly reflect expansive synovitis proliferation while galectin-3 is more closely linked to autoimmunity, smoking and joint destructive processes.

Doubling the single-dose infusion rate of tocilizumab in rheumatoid arthritis is safe and efficacious.

OBJECTIVES: To investigate the impact of enhanced infusion rate of tocilizumab on the occurrence of infusion reactions, overall safety, and efficacy in rheumatoid arthritis (RA). METHOD: We conducted a 24-week multicentre, open-label, randomized parallel group study comparing adverse event (AE) and effect profiles following tocilizumab IV 8 mg/kg every 4 weeks over 31 min vs. standard 60-min infusions in patients with RA and an inadequate clinical response to disease-modifying anti-rheumatic drugs (DMARDs) and/or tumour necrosis factor (TNF)-α inhibitors. RESULTS: A total of 47 patients were enrolled in the study and randomized to fast infusions (n = 25) and controls (n = 22). Incidences of infusion reactions were similar between the two groups, neither of them leading to withdrawal. Likewise, the incidence of additional AEs did not differ between the treatment arms. Two serious adverse events (SAEs) were reported, in the control group. Four patients withdrew due to AEs, two from each arm. Efficacy at week 24 was comparable between groups. CONCLUSIONS: In RA, monthly tocilizumab infusions of 8 mg/kg provided over 31 or 60 min during 24 weeks did not differ concerning safety or efficacy.

Prediction of treatment response to adalimumab: a double-blind placebo-controlled study of circulating microRNA in patients with early rheumatoid arthritis.

At least 30% of patients with rheumatoid arthritis (RA) do not respond to biologic agents, which emphasizes the need of predictive biomarkers. We aimed to identify microRNAs (miRNAs) predictive of response to adalimumab in 180 treatment-naïve RA patients enrolled in the OPtimized treatment algorithm for patients with early RA (OPERA) Study, an investigator-initiated, prospective, double-blind placebo-controlled study. Patients were randomized to adalimumab 40 mg (n=89) or placebo-adalimumab (n=91) subcutaneously in combination with methotrexate. Expressions of 377 miRNAs were determined using TaqMan Human MicroRNA LDA, A Card v2.0 (Applied Biosystems). Associations between miRNAs and treatment response were tested using interaction analyses. MiRNAs with a P-value <0.05 using three different normalizations were included in a multivariate model. After backwards elimination, the combination of low expression of miR-22 and high expression of miR-886.3p was associated with EULAR good response. Future studies to assess the utility of these miRNAs as predictive biomarkers are needed.

Circadian pattern and the effect of standardized physical exercise on procollagen IIA N-peptide (PIIANP) in rheumatoid arthritis at different stages and in healthy individuals.

BACKGROUND: Variant collagen IIA is re-expressed in diseased cartilage. Low procollagen IIA N-peptide (PIIANP) levels in serum have recently been reported in rheumatoid arthritis (RA). We investigated circadian rhythmicity and effect of physical activity on PIIANP in early and longstanding RA and in healthy subjects. METHODS: Patients with early and longstanding RA and controls were included. Fasting and serial blood samples were collected during 24 h. PIIANP response to physical activity was studied before and serially after standardized exercise. RESULTS AND CONCLUSION: In RA at different stages and healthy individuals, PIIANP exhibited no circadian rhythmicity, and PIIANP in serum was not influenced by physical activity.

Do changes in prescription practice in patients with rheumatoid arthritis treated with biological agents affect treatment response and adherence to therapy? Results from the nationwide Danish DANBIO Registry.

BACKGROUND: Prescription practice for tumour necrosis factor alpha (TNFalpha) inhibitors has changed towards treating patients with lower disease activity. OBJECTIVE: To determine the trend in treatment response in cohorts of patients with rheumatoid arthritis who started TNFalpha inhibitor treatment between 2000 and 2005. METHODS: 1813 patients with RA starting treatment with biological agents in 2000-5 were registered prospectively in the nationwide DANBIO Registry. Baseline disease activity and 12 months' treatment responses were determined in cohorts based on start year (2000/1; 2002; 2003; 2004; 2005). RESULTS: Despite decreasing baseline disease activity from the 2000/2001 cohort to 2005 cohort (28-joint count Disease Activity Score (DAS28): from 5.9 to 5.3 (p<0.001)), the 12 months' DAS improvement increased from 1.8 units (2000/2001 cohort) to 2.2 units (2005 cohort) (p<0.001). The fraction with good EULAR response increased from 28% (2000/2001 cohort) to 50% (2005 cohort); the fraction with no response decreased from 29% (2000/2001 cohort) to 16% (2005 cohort). ACR20/50/70 response rates increased from 53%/31%/13% (2000/2001 cohort) to 69%/51%/30% (2005 cohort). After correction for withdrawals, treatment responses were lower, but patterns unchanged. One-year drug survival was for the 2000/2001 cohort: 73%, 2002: 62%, 2003: 67%, 2004: 70%, 2005: 69%. CONCLUSION: From 2000 to 2005, significantly improved treatment responses to TNF inhibitors were seen in clinical practice despite decreasing baseline disease activity levels. This lends support to the less stringent prescription practice towards treating patients with lower disease activity that has been observed in several countries.

Circulating surfactant protein D is decreased in early rheumatoid arthritis: a 1-year prospective study.

Innate immune system abnormalities, e.g., mannan-binding lectin (MBL) genotype variants, have been demonstrated to modify the disease course of rheumatoid arthritis (RA). Surfactant protein D (SP-D) shares important structural and functional properties with MBL suggesting that SP-D may be an additional RA disease modifier. The Met11Thr polymorphism in the N-terminal part of SP-D is an important determinant for the SP-D serum level, but this polymorphism is also essential to the function and assembly into oligomers. We aimed to compare the serum levels of SP-D in a cohort of newly diagnosed untreated RA patients with healthy matched controls, and to investigate if there was an association to core measures of disease activity within the first year after disease onset. Secondly, we aimed to investigate whether the Met11Thr polymorphism was associated with RA. Serum SP-D was significantly lower in DMARD naive RA patients compared with healthy controls (P = 0.016). Median SP-D concentration at inclusion was 878 ng/ml (95% CI: 730-1033) and 1164 ng/ml (95% CI: 1093-1366) in RA patients and matched controls, respectively. SP-D increased during Methotrexate treatment (P < 0.0001), and at 1-year follow-up median SP-D was 1032 ng/ml (95% CI: 777-1255). SP-D levels did not correlate with traditional disease activity measures. The Thr11/Thr11 genotype and the Thr11 allele tended to be more frequent in RA patients. In conclusion, the low serum level of SP-D and the lack of correlation with traditional disease activity measures indicate that SP-D reflects a distinctive aspect in the RA pathogenesis.

Low-cost, low-field dedicated extremity magnetic resonance imaging in early rheumatoid arthritis: a 1-year follow-up study.

OBJECTIVE: To study the ability of low-cost low-field dedicated extremity magnetic resonance imaging (E-MRI) to assess and predict erosive joint damage in the wrist and metacarpophalangeal (MCP) joints of patients with early rheumatoid arthritis. METHODS: 24 previously untreated patients with rheumatoid arthritis with joint symptoms for <1 year were evaluated at the time of diagnosis and after 6 and 12 months of methotrexate treatment with conventional clinical or biochemical examinations, x rays of both hands and wrists, and E-MRI of the dominant wrist and MCP joints. RESULTS: At baseline, all patients showed magnetic resonance imaging (MRI) synovitis, and MRI erosions were detected in 21 bones (10 patients). 6 (29%) of these, distributed among two patients, were seen on x ray. One x ray erosion was not detected by MRI. At 1 year, MRI and x ray detected 15 and 8 new erosions, respectively, and 19% of MRI erosions at baseline had progressed to x ray erosions. In bones with MRI erosions at baseline, the relative risk of having x ray erosions at the 1-year follow-up was 12.1, compared with bones without baseline MRI erosions (lesion-centred analysis). If bones with baseline x ray erosions were excluded, the relative risk was 5.2. In patients with baseline MRI bone erosion or oedema, the relative risk of having x ray erosions at 1 year was 4.0, compared with patients without these signs at baseline (patient-centred analysis). CONCLUSION: In this group of patients with early rheumatoid arthritis who were treated uniformly, baseline E-MRI erosions in MCP or wrist bones markedly increased the risk of x ray erosions at the 1-year follow-up. Low-cost, low-field dedicated extremity MRI is promising for assessment and prognostication of early rheumatoid arthritis.