Abstract
Background:
Accurate measurements of rheumatoid factors (RFs), autoantibodies binding IgG, are important for diagnosing rheumatoid arthritis (RA) and for predicting disease course. ...Worldwide, various RF assays are being used that differ in technique and target antigens. We studied whether assay choice leads to clinically important discrepancies in RF status and level.
Methods:
RF measurements using four commercial RF assays were compared in 32 RF
+
samples. Using enzyme-linked immunosorbent assays (ELISAs), the influence of the target antigen source – human IgG (hIgG) versus rabbit IgG (rIgG) – on measured RF levels was investigated in arthralgia patients and RA patients.
Results:
Substantial discrepancies were found between RF levels measured in the four commercial assays. Six samples (19%) with RF levels below or slightly above the cutoff in the rIgG-based Phadia assay were RF
+
in three assays using hIgG as the target antigen, some with very high levels. Direct ELISA comparisons of RF reactivity against hIgG and rIgG estimated that among 173 ACPA
+
arthralgia patients, originally RF negative in rIgG-based assays, up to 10% were single positive against hIgG. Monoclonal RFs binding to hIgG and rIgG or hIgG only supported these findings. In a cohort of 69 early RA patients, virtually all RF responses reacted with both targets, although levels were still variable.
Conclusions:
The use of RF assays that differ in technique and target antigen, together with the different specificities of RF responses, leads to discrepancies in RF status and levels. This has important consequences for patient care if RA diagnosis and disease progression assessments are based on RF test results.
Rheumatoid arthritis (RA) is a complex genetic disorder in which the HLA-region contributes most to the genetic risk. HLA-DRB1-molecules containing the amino acid sequence DERAA (i.e., HLA-DRB1*0103, ...*0402, *1102, *1103, *1301, *1302, and *1304) are associated with protection from RA. It has been proposed that not only inherited but also noninherited HLA-antigens from the mother (NIMA) can influence RA-susceptibility. Up to now, no protective NIMAs were described. Here, we studied whether DERAA-containing HLA-DRB1-alleles as NIMA are associated with a protective effect. One hundred seventy-nine families were studied, 88 from the Netherlands and 91 from the United Kingdom. The frequency of DERAA-containing HLA-DRB1-alleles of the Dutch mothers (16.1%), but not of the fathers (26.2%), was lower compared with the general Dutch population (29.3%; P = 0.02). This was replicated in the English set of patients and controls (P = 0.01). Further, of all families, 45 contained at least one DERAA-negative child with RA and at least one DERAA-positive parent. The odds for the DERAA-negative RA patients of having a DERAA-positive mother was significantly lower compared with having a DERAA-positive father (OR 0.25; P = 0.003). These data show a protective NIMA-effect in a human autoimmune disease and indicate that a DERAA-positive mother can transfer protection against RA to her DERAA-negative child.
Full text
Available for:
BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The type I interferon (IFN) signature in rheumatoid arthritis (RA) has shown clinical relevance in relation to disease onset and therapeutic response. Identification of the cell type(s) contributing ...to this IFN signature could provide insight into the signature's functional consequences. The aim of this study was to investigate the contribution of peripheral leukocyte subsets to the IFN signature in early arthritis.
Blood was collected from 26 patients with early arthritis and lysed directly or separated into peripheral blood mononuclear cells (PBMCs) and polymorphonuclear granulocytes (PMNs). PBMCs were sorted into CD4(+) T cells, CD8(+) T cells, CD19(+) B cells, and CD14(+) monocytes by flow cytometry. Messenger RNA expression of three interferon response genes (IRGs RSAD2, IFI44L, and MX1) and type I interferon receptors (IFNAR1 and IFNAR2) was determined in whole blood and blood cell subsets by quantitative polymerase chain reaction. IRG expression was averaged to calculate an IFN score for each sample.
Patients were designated "IFN(high)" (n = 8) or "IFN(low)" (n = 18) on the basis of an IFN score cutoff in whole peripheral blood from healthy control subjects. The difference in IFN score between IFN(high) and IFN(low) patients was remarkably large for the PMN fraction (mean 25-fold) compared with the other subsets (mean 6- to 9-fold), indicating that PMNs are the main inducers of IRGs. Moreover, the relative contribution of the PMN fraction to the whole-blood IFN score was threefold higher than expected from its abundance in blood (p = 0.008), whereas it was three- to sixfold lower for the other subsets (p ≤ 0.063), implying that the PMNs are most sensitive to IFN signaling. Concordantly, IFNAR1 and IFNAR2 were upregulated compared with healthy controls selectively in patient PMNs (p ≤ 0.0077) but not in PBMCs.
PMNs are the main contributors to the whole-blood type I IFN signature in patients with early arthritis, which seems due to increased sensitivity of these cells to type I IFN signaling. Considering the well-established role of neutrophils in the pathology of arthritis, this suggests a role of type I IFN activity in the disease as well.
ObjectivesPersons at high risk of rheumatoid arthritis (RA) might benefit from a low-risk pharmacological intervention aimed at primary prevention. Previous studies demonstrated disease-modifying ...effects of statins in patients with RA as well as an association between statin use and a decreased risk of RA development. A randomised, double-blind, placebo-controlled trial investigated whether atorvastatin could prevent arthritis development in high-risk individuals.MethodsArthralgia patients with anticitrullinated protein antibody (ACPA) >3 xULN or ACPA and rheumatoid factor, without (a history of) arthritis, were randomised to receive atorvastatin 40 mg daily or placebo for 3 years. The calculated sample size was 220 participants. The primary endpoint was clinical arthritis. Cox regression analysis was used to determine the effect of atorvastatin on arthritis development.ResultsDue to a low inclusion rate, mainly because of an unwillingness to participate, the trial was prematurely stopped. Data of the 62 randomised individuals were analysed. Median follow-up was 14 (inner quartiles 6–35) months. Fifteen individuals (24%) developed arthritis: 9/31 (29%) in the atorvastatin group; 6/31 (19%) in the placebo group: HR 1.40, 95% CI 0.50 to 3.95.ConclusionsIn this small set of randomised high-risk individuals, we did not demonstrate a protective effect of atorvastatin on arthritis development. The main reason for the low inclusion was unwillingness to participate; this may also impede other RA prevention trials. Further research to investigate and solve barriers for prevention trial participation is needed.
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.
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.
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.
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.
Workers with rheumatoid arthritis (RA) often experience restrictions in functioning at work and participation in employment. Strategies to maintain work productivity exist, but these interventions do ...not involve the actual workplace. Therefore the aim of this study is to investigate the (cost)effectiveness of an intervention program at the workplace on work productivity for workers with RA.
This study is a randomized controlled trial (RCT) in specialized rheumatology treatment centers in or near Amsterdam, the Netherlands. Randomisation to either the control or the intervention group is performed at patient level. Both groups will receive care as usual by the rheumatologist, and patients in the intervention group will also take part in the intervention program. The intervention program consists of two components; integrated care, including a participatory workplace intervention. Integrated care involves a clinical occupational physician, who will act as care manager, to coordinate the care. The care manager has an intermediate role between clinical and occupational care. The participatory workplace intervention will be guided by an occupational therapist, and involves problem solving by the patient and the patients' supervisor. The aim of the workplace intervention is to achieve consensus between patient and supervisor concerning feasible solutions for the obstacles for functioning at work. Data collection will take place at baseline and after 6 and 12 months by means of a questionnaire. The primary outcome measure is work productivity, measured by hours lost from work due to presenteeism. Secondary outcome measures include sick leave, quality of life, pain and fatigue. Cost-effectiveness of the intervention program will be evaluated from the societal perspective.
Usual care of primary and outpatient health services is not aimed at improving work productivity. Therefore it is desirable to develop interventions aimed at improving functioning at work. If the intervention program will be (cost)effective, substantial improvements in work productivity might be obtained among workers with RA at lower costs. Results are expected in 2015.
NTR2886.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
To evaluate the prevalence and 8‐year course of forefoot impairments and walking disability in patients with rheumatoid arthritis (RA).
Methods
A total of 848 patients with recent‐onset RA ...from 1995 through the present were included. The patients were assessed annually. Pain and swelling of the metatarsophalangeal (MTP) joints, erosions and joint space narrowing of the MTP joints and first interphalangeal joints, and the Health Assessment Questionnaire walking subscale were analyzed using descriptive and correlational techniques.
Results
Pain and swelling of ≥1 MTP joint was present in 70% of patients at baseline, decreasing to ∼40–50% after 2 years. The forefoot erosion score was ≥1 in 19% of the patients at baseline, and the prevalence of forefoot erosion increased to ∼60% after 8 years, during which the mean forefoot erosion score increased from 1.3 to 7.9. At least mild walking disability was present in 57% of patients at baseline, stabilizing at ∼40% after 1 year.
Conclusion
The prevalence rates for pain and swelling of the MTP joints and walking disability are initially high and then stabilize, but the prevalence and severity of forefoot joint damage increase during an 8‐year course of RA. The findings of this study quantitatively emphasize the importance of forefoot involvement in patients with RA.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Multiple lymphocyte subsets like T and B cells have been connected to joint infiltration and inflammation in rheumatoid arthritis (RA). Identification of leucocyte subsets that are dysregulated in ...arthritis development could provide insight into the aetiology of RA. This study aimed to investigate the composition of the peripheral blood components, i.e. CD14(+) monocytes, CD4(+) and CD8(+) T lymphocytes (CD3(+)), CD80(+), C-X-C chemokine receptor 3 (CXCR3)(+) and CD27(+) B lymphocytes (CD19(+)), CD16(+)CD56(+)CD3(-) natural killer (NK) cells and activated CD56(+)CD3(+) T cells, for association with arthritis development in patients with arthralgia.
Peripheral blood was collected from 89 patients with early RA (disease duration <6 months), 37 healthy controls (HC) and 113 patients with arthralgia (22 developed arthritis within ≤1 year, 18 developed arthritis after >1 year and 73 did not develop arthritis). Absolute numbers of monocytes and lymphocyte subsets in whole heparinized blood were determined with flow cytometry using quantification beads in combination with fluorescent labelled antibodies for T cells, B cells, monocytes, NK cells and activated T cells.
In patients with early RA, significant decreases in numbers of (activated) T cells, CD80(+) and memory B cells and a trend towards smaller numbers of CD8(+) T cells was observed compared to HC. Similar differences were seen in patients with arthralgia who developed or did not develop arthritis (non-converters), with significantly decreased CD8(+) T cells and memory B cells. Patients with arthralgia who developed arthritis were split into groups that developed arthritis within 1 year (early converters) or after 1 year (late converters). Late converters had a significantly decreased number of CD8(+) T cells compared to non-converters; early converters had a decreased number of memory B cells. Longitudinal analysis of converters showed a significant relative increase in CD80(+) B cells towards the conversion time point compared to 24 months prior to conversion.
This study revealed that patients with arthralgia who develop arthritis demonstrate a change in cellular immune parameters apparent in the periphery, starting with a decrease in cytotoxic T cells 24 months prior to arthritis development, followed by a decrease in the number of memory B cells 12 months prior to disease onset.
PDF
