Autoantibody systems in rheumatoid arthritis: specificity, sensitivity and diagnostic value

The diagnosis of rheumatoid arthritis (RA) is primarily based on clinical symptoms, so it is often difficult to diagnose RA in very early stages of the disease. A disease-specific autoantibody that could be used as a serological marker would therefore be very useful. Most autoimmune diseases are characterized by a polyclonal B-cell response targeting multiple autoantigens. These immune responses are often not specific for a single disease. In this review, the most important autoantibody/autoantigen systems associated with RA are described and their utility as a diagnostic and prognostic tool, including their specificity, sensitivity and practical application, is discussed. We conclude that, at present, the antibody response directed to citrullinated antigens has the most valuable diagnostic and prognostic potential for RA.     

Autoantibody systems in rheumatoid arthritis: specificity, sensitivity and diagnostic value

The diagnosis of rheumatoid arthritis (RA) is primarily based on clinical symptoms, so it is often difficult to diagnose RA in very early stages of the disease. A disease-specific autoantibody that could be used as a serological marker would therefore be very useful. Most autoimmune diseases are characterized by a polyclonal B-cell response targeting multiple autoantigens. These immune responses are often not specific for a single disease. In this review, the most important autoantibody/autoantigen systems associated with RA are described and their utility as a diagnostic and prognostic tool, including their specificity, sensitivity and practical application, is discussed. We conclude that, at present, the antibody response directed to citrullinated antigens has the most valuable diagnostic and prognostic potential for RA.     

Autoantibody profile in rheumatoid arthritis during long-term infliximab treatment

The aim of the present study was to investigate the effect of long-term infliximab treatment on various autoantibodies in patients with rheumatoid arthritis. Serum samples from 30 consecutive patients, who were prospectively followed during infliximab and methotrexate therapy for refractory rheumatoid arthritis, were tested at baseline and after 30, 54 and 78 weeks. At these points, median values of the Disease Activity Score were 6.38 (interquartile range 5.30–6.75), 3.69 (2.67–4.62), 2.9 (2.39–4.65) and 3.71 (2.62–5.06), respectively. Various autoantibodies were assessed by standard indirect immunofluorescence and/or ELISA. Initially, 50% of patients were positive for antinuclear antibodies, and this figure increased to 80% after 78 weeks (P = 0.029). A less marked, similar increase was found for IgG and IgM anticardiolipin antibody titre, whereas the frequency of anti-double-stranded DNA antibodies (by ELISA) exhibited a transient rise (up to 16.7%) at 54 weeks and dropped to 0% at 78 weeks. Antibodies to proteinase-3 and myeloperoxidase were not detected. The proportion of patients who were positive for rheumatoid factor (RF) was similar at baseline and at 78 weeks (87% and 80%, respectively). However, the median RF titre exhibited a progressive reduction from 128 IU/ml (interquartile range 47–290 IU/ml) to 53 IU/ml (18–106 IU/ml). Anti-cyclic citrullinated peptide (CCP) antibodies were found in 83% of patients before therapy; anti-CCP antibody titre significantly decreased at 30 weeks but returned to baseline thereafter. In conclusion, the presence of anti-double-stranded DNA antibodies is a transient phenomenon, despite a stable increase in antinuclear and anticardiolipin antibodies. Also, the evolution of RF titres and that of anti-CCP antibody titres differed during long-term infliximab therapy.     

Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis

Rheumatoid arthritis (RA) is a prototypical autoimmune arthritis affecting nearly 1% of the world population and is a significant cause of worldwide disability. Though prior studies have demonstrated the appearance of RA-related autoantibodies years before the onset of clinical RA, the pattern of immunologic events preceding the development of RA remains unclear. To characterize the evolution of the autoantibody response in the preclinical phase of RA, we used a novel multiplex autoantigen array to evaluate development of the anti-citrullinated protein antibodies (ACPA) and to determine if epitope spread correlates with rise in serum cytokines and imminent onset of clinical RA. To do so, we utilized a cohort of 81 patients with clinical RA for whom stored serum was available from 1-12 years prior to disease onset. We evaluated the accumulation of ACPA subtypes over time and correlated this accumulation with elevations in serum cytokines. We then used logistic regression to identify a profile of biomarkers which predicts the imminent onset of clinical RA (defined as within 2 years of testing). We observed a time-dependent expansion of ACPA specificity with the number of ACPA subtypes. At the earliest timepoints, we found autoantibodies targeting several innate immune ligands including citrullinated histones, fibrinogen, and biglycan, thus providing insights into the earliest autoantigen targets and potential mechanisms underlying the onset and development of autoimmunity in RA. Additionally, expansion of the ACPA response strongly predicted elevations in many inflammatory cytokines including TNF-α, IL-6, IL-12p70, and IFN-γ. Thus, we observe that the preclinical phase of RA is characterized by an accumulation of multiple autoantibody specificities reflecting the process of epitope spread. Epitope expansion is closely correlated with the appearance of preclinical inflammation, and we identify a biomarker profile including autoantibodies and cytokines which predicts the imminent onset of clinical arthritis.     

CCP、AKA、APF联合RF检测对类风湿性关节炎的诊断意义

目的 探究抗环瓜氨酸肽（CCP）抗体、抗角质蛋白（AKA）抗体、抗核周围因子（APF）抗体联合类风湿因子（RF）检测对类风湿性关节炎（RA）的临床诊断价值。方法 检测94例RA患者和69例非RA自身免疫疾病患者血清中该4项指标,并将该4种指标的敏感度、特异度、阳性预测值以及阴性预测值进行比对分析。结果 RA组患者该4项指标的阳性率均明显高于非RA组（P<0.05）。RA组中CCP、AKA、APF和RF的敏感度分别为79.79%、45.74%、48.94%、75.53%,特异性分别为95.65%、94.20%、91.30%、79.71%,其中抗CCP与RF比较差异有统计学意义（P<0.05）。RA组中CCP、AKA、APF和RF阳性预测值分别为96.15%、91.49%、88.46%、83.53%。4项指标联合检测中,任一指标阳性即判定RA阳性的敏感度为89.36%,4项指标均为阳性即判定RA阳性的特异度高达98.55%,阳性预测值达96.77%。结论 抗CCP抗体具有较高的灵敏度和特异性。4项指标联合检测可提高RA诊断的准确性,有利于RA患者早期诊断和治疗。     

Possible rheumatoid arthritis subtypes in terms of rheumatoid factor,depression, diagnostic delay and emotional expression: an exploratory case-control study

Introduction

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathology of rheumatoid arthritis (RA), particularly as vulnerable personality types are exposed to chronic stress. Emotions are powerful modulators of stress responses. However, little is known about whether patients with RA process emotions differently to matched controls. In this study we: 1) assessed whether the trait emotional intelligence (trait EI) scores of patients with RA differ from healthy controls at the facet level; 2) explored any subgroups in RA, in terms of trait EI and common risk factors.

Methods

A total of 637 patients with RA were compared to 496 controls on the trait EI Questionnaire (TEIQue). RA subgroups were explored in terms of trait EI, rheumatoid factor status (RF+/-), depression and time from onset of symptoms until diagnosis (diagnostic delay).

Results

The RA group rated themselves lower on Adaptability, Stress-management, Emotion management, Self-esteem, Sociability, Assertiveness, Impulsiveness and Well-being, and higher on Empathy and Relationships than healthy controls. The RF- subtype reported more time with depression (25.2 vs. 11.3 months), a longer diagnostic delay (3.0 vs. 1.7 years), and greater emotional expression (5.15 vs. 4.72), than the RF+ subtype. These differences were significant at the P <0.05 level, but not following strict Bonferroni corrections and should therefore be treated as indicative only. RF- patients with a longer diagnostic delay reported depression lasting three times longer (42.7 months), when compared to three other subtypes (11.0 to 12.7 months).

Conclusions

RA patients and controls differ in their emotion-related personality traits, as operationalized by trait EI. These differences may make people with RA more susceptible to chronic stress and HPA-axis dysregulation. RA may be a highly heterogeneous illness where at least two subtypes may be characterized by personality, psychiatric and immunological differences. RF- status, as well as diagnostic delay and emotional expression, may predict future risk of depression. Research on the causes of RA could benefit from a systems science approach.     

The value of sensitive imaging modalities in rheumatoid arthritis

X-ray evaluation of rheumatoid joints is relatively inexpensive, is widely available and has standardised methods for interpretation. It also has limitations, including the inability to reliably determine structural change in less than 6-12 months, the need for experienced readers to interpret images and the limited acceptance of this technique in routine clinical practice. High-frequency ultrasound, with or without power Doppler, and magnetic resonance imaging of rheumatoid joints permit an increasingly refined analysis of anatomic detail. However, further research using these sensitive imaging technologies is required to delineate pathophysiological correlates of imaging abnormalities and to standardise methods for assessment.     

Inter-observer agreement,diagnostic sensitivity and specificity of animal-based indicators of young lamb welfare

A scientific literature review and consensus of expert opinion used the welfare definitions provided by the Farm Animal Welfare Council (FAWC) Five Freedoms as the framework for selecting a set of animal-based indicators that were sensitive to the current on-farm welfare issues of young lambs (aged ⩽6 weeks). Ten animal-based indicators assessed by observation – demeanour, response to stimulation, shivering, standing ability, posture, abdominal fill, body condition, lameness, eye condition and salivation were tested as part of the objective of developing valid, reliable and feasible animal-based measures of lamb welfare The indicators were independently tested on 966 young lambs from 17 sheep flocks across Northwest England and Wales during December 2008 to April 2009 by four trained observers. Inter-observer reliability was assessed using Fleiss's kappa (κ), and the pair-wise agreement with an experienced, observer designated as the ‘test standard observer’ (TSO) was examined using Cohen's κ. Latent class analysis (LCA) estimated the sensitivity (Se) and specificity (Sp) of each observer without assuming a gold standard and predicted the Se and Sp of randomly selected observers who may apply the indicators in the future. Overall, good levels of inter-observer reliability, and high levels of Sp were identified for demeanour (κ = 0.54, Se ⩾ 0.70, Sp ⩾ 0.98), stimulation (κ = 0.57, Se = 0.30 to 0.77, Sp ⩾ 0.98), shivering (κ = 0.55, Se = 0.37 to 0.85, Sp ⩾ 0.99), standing ability (0.54, Se ⩾ 0.80, Sp ⩾ 0.99), posture (κ = 0.45, Se ⩾ 0.56, Sp = 0.99), abdominal fill (κ = 0.44, Se = 0.39 to 0.98, Sp = 0.99), body condition (κ = 0.72, Se ⩾ 0.38 to 0.90, Sp = 0.99), lameness (κ = 0.68, Se > 0.73, Sp = 1.00), and eye condition (κ = 0.72, Se ⩾ 0.86, Sp = 0.99). LCA predicted that randomly selected observers had Se > 0.77 (acceptable), and Sp ⩾ 0.98 (high) for assessments of demeanour, lameness, abdominal fill posture, body condition and eye condition. The diagnostic performance of some indicators was influenced by the composition of the study population, and it would be useful to test the indicators on lambs with a greater level of outcomes associated with poor welfare. The findings presented in this paper could be applied in the selection of valid, reliable and feasible indicators used for the purposes of on-farm assessments of lamb welfare.     

Rheumatoid factors: value of their determination in patients with rheumatoid arthritis

IgM, IgA, IgG rheumatoid factors were investigated by a indirect immunofluorescence method in three groups of patients affected with rheumatoid arthritis of various picture: 30 patients with mild articular disease, 20 with severe joint involvement and 19 with articular and systemic symptoms. Rheumatoid factors occurred more frequently in patients with articular and extraarticular severe rheumatoid arthritis; moreover these patients showed higher titres and higher incidence of different immunoglobulin class rheumatoid factors in comparison with rheumatoid patients having mild joint disease.     

Novel multiplex technology for diagnostic characterization of rheumatoid arthritis

Introduction  

The aim of this study was to develop a clinical-grade, automated, multiplex system for the differential diagnosis and molecular stratification of rheumatoid arthritis (RA).     

The relationship between disease activity, sleep, psychiatric distress and pain sensitivity in rheumatoid arthritis: a cross-sectional study

Introduction  

Despite recent advances in anti-inflammatory therapy, rheumatoid arthritis (RA) patients continue to rate pain as a priority. The etiology of RA pain is likely multifactorial, including both inflammatory and non-inflammatory components. In this study, we examine the association between disease activity, sleep, psychiatric distress and pain sensitivity in RA.     

The relationship between disease activity, sleep, psychiatric distress and pain sensitivity in rheumatoid arthritis: a cross-sectional study

Introduction

Cell stimulation leads to the shedding of phosphatidylserine (PS)-rich microparticles (MPs). Because autoimmune diseases (AIDs) are characterized by cell activation, we investigated level of circulating MPs as a possible biomarker in primary Sjögren's syndrome (pSS), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).

Methods

We measured plasma levels of total, platelet and leukocyte MPs by prothrombinase capture assay and flow cytometry in 43 patients with pSS, 20 with SLE and 24 with RA and in 44 healthy controls (HCs). Secretory phospholipase A2 (sPLA2) activity was assessed by fluorometry. Soluble CD40 ligand (sCD40L) and soluble P-selectin (sCD62P), reflecting platelet activation, were measured by ELISA.

Results

Patients with pSS showed increased plasma level of total MPs (mean ± SEM 8.49 ± 1.14 nM PS equivalent (Eq), P < 0.0001), as did patients with RA (7.23 ± 1.05 n PS Eq, P = 0.004) and SLE (7.3 ± 1.25 nM PS Eq, P = 0.0004), as compared with HCs (4.13 ± 0.2 nM PS Eq). Patients with AIDs all showed increased level of platelet MPs (P < 0.0001), but only those with pSS showed increased level of leukocyte MPs (P < 0.0001). Results by capture assay and flow cytometry were correlated. In patients with high disease activity according to extra-glandular complications (pSS), DAS28 (RA) or SLEDAI (SLE) compared with low-activity patients, the MP level was only slightly increased in comparison with those having a low disease activity. Platelet MP level was inversely correlated with anti-DNA antibody level in SLE (r = -0.65; P = 0.003) and serum β2 microglobulin level in pSS (r = -0.37; P < 0.03). The levels of total and platelet MPs were inversely correlated with sPLA2 activity (r = -0.37, P = 0.0007; r = -0.36, P = 0.002, respectively). sCD40L and sCD62P concentrations were significantly higher in pSS than in HC (P ≤ 0.006).

Conclusions

Plasma MP level is elevated in pSS, as well as in SLE and RA, and could be used as a biomarker reflecting systemic cell activation. Level of leukocyte-derived MPs is increased in pSS only. The MP level is low in case of more severe AID, probably because of high secretory phospholipase A2 (sPLA2) activity, which leads to consumption of MPs. Increase of platelet-derived MPs, sCD40L and sCD62P, highlights platelet activation in pSS.     

The sensitivity, specificity and predictive value of measuring calcium carbonate in mares' prepartum mammary secretions

A colorimetric test kit marketed for water quality analysis was used to measure calcium carbonate changes in diluted prefoaling mammary secretions. Daily samples (1 to 3 ml/day) were obtained from 59 Thoroughbred and Warmblood mares starting 14 days prior to foaling to the day of parturition. The sensitivity, specificity, and positive and negative predictive values of the test were calculated on the data collected from 56 mares and 377 prefoaling mammary secretion samples. The results indicate that this test is both sensitive and specific. The predictive value of a positive test (PVPT; positive test defined as the first occurrence that prefoaling mammary secretion calcium carbonate >/= 200 ppm) indicated that 51.4% of late term pregnant mares would foal within the ensuing 24-hour period, 84.1% within 48 hours and 97.2% within 72 hours. The predictive value of a negative test (PVNT; negative test defined as prefoaling mammary secretion calcium carbonate < 200 ppm) indicated that 99.6% of late term pregnant mares would not be expected to foal within the ensuing 24 hour period, % within 48 hours and 81.8% within 72 hours. This test is helpful as a prognostic tool in indicating the mare's approaching readiness for birth. It is also an accurate prognostic tool to predict that the mare is not likely to foal within 24h when calcium carbonate < 200 ppm in the diluted prefoaling mammary secretion.     

A cross-sectional study of pain sensitivity,disease-activity assessment,mental health,and fibromyalgia status in rheumatoid arthritis

IntroductionPain remains the most important problem for people with rheumatoid arthritis (RA). Active inflammatory disease contributes to pain, but pain due to non-inflammatory mechanisms can confound the assessment of disease activity. We hypothesize that augmented pain processing, fibromyalgic features, poorer mental health, and patient-reported 28-joint disease activity score (DAS28) components are associated in RA.MethodsIn total, 50 people with stable, long-standing RA recruited from a rheumatology outpatient clinic were assessed for pain-pressure thresholds (PPTs) at three separate sites (knee, tibia, and sternum), DAS28, fibromyalgia, and mental health status. Multivariable analysis was performed to assess the association between PPT and DAS28 components, DAS28-P (the proportion of DAS28 derived from the patient-reported components of visual analogue score and tender joint count), or fibromyalgia status.ResultsMore-sensitive PPTs at sites over or distant from joints were each associated with greater reported pain, higher patient-reported DAS28 components, and poorer mental health. A high proportion of participants (48%) satisfied classification criteria for fibromyalgia, and fibromyalgia classification or characteristics were each associated with more sensitive PPTs, higher patient-reported DAS28 components, and poorer mental health.ConclusionsWidespread sensitivity to pressure-induced pain, a high prevalence of fibromyalgic features, higher patient-reported DAS28 components, and poorer mental health are all linked in established RA. The increased sensitivity at nonjoint sites (sternum and anterior tibia), as well as over joints, indicates that central mechanisms may contribute to pain sensitivity in RA. The contribution of patient-reported components to high DAS28 should inform decisions on disease-modifying or pain-management approaches in the treatment of RA when inflammation may be well controlled.     

Association of MHC and rheumatoid arthritis: HLA polymorphisms in phenotypic variants of rheumatoid arthritis

Genes in the human leukocyte antigen (HLA) region remain the most powerful disease risk genes in rheumatoid arthritis (RA). Several allelic variants of HLA-DRB1 genes have been associated with RA, supporting a role for T-cell receptor-HLA-antigen interactions in the pathologic process. Disease-associated HLA-DRB1 alleles are similar but not identical and certain allelic variants are preferentially enriched in patient populations with defined clinical characteristics. Also, a gene dosing effect of HLA-DRB1 alleles has been suggested by the accumulation of patients with two RA-associated alleles, especially in patient subsets with a severe disease course. Therefore, polymorphisms in HLA genes are being explored as tools to dissect the clinical heterogeneity of the rheumatoid syndrome. Besides HLA polymorphisms, other risk genes will be helpful in defining genotypic profiles correlating with disease phenotypes. One such phenotype is the type of synovial lesion generated by the patient. HLA genes in conjunction with other genetic determinants may predispose patients to a certain pathway of synovial inflammation. Also, patients may or may not develop extraarticular manifestations, which are critical in determining morbidity and mortality. HLA genes, complemented by other RA risk genes, are likely involved in shaping the T-cell repertoire, including the emergence of an unusual T-cell population characterized by the potential of vascular injury, such as seen in extraarticular RA.     

Association of MHC and rheumatoid arthritis. HLA-DR4 and rheumatoid arthritis: studies in mice and men

Inherited susceptibility to rheumatoid arthritis (RA) is associated with the DRB1 genes encoding the human leukocyte antigen (HLA)-DR4 and HLA-DR1 molecules. Transgenic mice expressing these major histocompatibility complex (MHC) class II molecules have been developed to generate humanized models for RA. The relevance of these models for understanding RA will be discussed.     

Stress in seabirds: causes, consequences and diagnostic value

We describe a range of anthropogenic stressors thatimpact seabirds, review the effects of these stressorson individuals and populations and discuss the roleand value of seabirds as monitors of marine ecosystemhealth. Stressors described are restricted to thosewhich affect seabirds directly or indirectly throughthe marine environment; we have not dealt withterrestrially based stressors such as introducedmammalian predators or loss of habitat, which canpotentially affect seabirds whilst breeding. Wediscuss three broad categories of stress in seabirds.Marine pollutants (including biologicallynon-essential heavy metals, oil, organic pesticidesand polychlorinated biphenyls (PCBs), and plastics),industrial fisheries (further divided into the effectsof depletion of prey stocks and direct mortality), andclimate change. Additionally we highlight the role ofseabirds as monitors of marine ecosystem health,taking the example of long-term mercury contaminationas a case study. We conclude that seabirds are exposedto an increasing array of potential stressors, andthat the impact of a particular source of stress onseabirds varies markedly between species in relationto foraging and breeding ecology. The most seriousthreat to seabirds is direct mortality of adultsresulting from industrial and commercial fishingactivities. In some cases this is a significant threatto individual populations or even entire species.     

Diagnostic value of antibodies against a modified citrullinated vimentin in rheumatoid arthritis

Antibodies directed against citrullinated vimentin are members of the family of autoantibodies reactive with citrullinated proteins and are among the most specific serological markers for the diagnosis of rheumatoid arthritis (RA). This study was performed to test the diagnostic value of a newly developed enzyme-linked immunosorbent assay (ELISA) for the detection of antibodies against a genetically modified citrullinated vimentin (anti-MCV) in comparison with a second-generation anti-cyclic citrullinated peptides (anti-CCP2) ELISA test system. Blinded sera from 631 patients (409 consecutive out-patients and 222 randomly selected stored sera) with RA (n = 164) and non-RA (osteoarthritis [n = 120], polymyalgia rheumatica/giant cell arteritis [n = 80], spondyloarthritis [n = 36], and other inflammatory rheumatic or non-inflammatory disease [n = 67]) were tested for the presence of anti-MCV and anti-CCP2 antibodies according to the manufacturers' instructions. The diagnostic performance of the anti-MCV was comparable with the anti-CCP2 assay for the diagnosis of RA according to the calculated area under the curve (0.824; 95% confidence interval (CI) 0.778-0.870 versus 0.818; 95% CI 0.767-0.869) as analysed by receiving operating characteristic curve. When categorised with a cutoff value of 20.0 U/ml (as recommended by the manufacturer), sensitivity and specificity of the anti-MCV ELISA were 69.5% (95% CI 61.9%-76.5%) and 90.8% (86.9%-93.8%), respectively, compared with 70.1% (62.5%-77.0%) and 98.7% (96.7%-99.6%) of the anti-CCP2 assay. Using the cutoff values of 19.0 U/ml and 81.5 U/ml for the anti-MCV test to obtain a sensitivity and specificity identical to the anti-CCP2 assay, showed a reduced specificity (89.8%; 85.8%-92.9%) and sensitivity (53.7%; 45.7%-61.5%), respectively, of the anti-MCV ELISA compared with the anti-CCP2 test. In conclusion, the serum ELISA testing for anti-MCV antibodies as well as the anti-CCP-2 assay perform comparably well in the diagnosis of RA. In the high-specificity range, however, the anti-CCP2 assay appears to be superior to the anti-MCV test.     

Cytokines in rheumatoid arthritis: trials and tribulations

Biological agents that inhibit the activity of proinflammatory cytokines are being investigated for use in the treatment of rheumatoid arthritis. Thus far, two of these agents, both of which neutralize tumor necrosis factor alpha (TNF-alpha), have received US Food and Drug Administration approval for the treatment of the disease. Etanercept is a bioengineered fusion protein of the p75 soluble TNF receptor, and infliximab is a chimeric monoclonal antibody to TNF-alpha. Other agents that target proinflammatory cytokines are also being developed. By allowing earlier treatment and better-tolerated long-term therapy, biologics might help slow or prevent disease progression and joint destruction.