Peptidyl-arginine deiminase-type IV as a diagnostic and prognostic marker in rheumatoid arthritis patients

Aim of the work

To measure serum peptidyl arginine deiminase (PADI4) enzyme level in rheumatoid arthritis (RA) patients and to assess its role in diagnosis and monitoring patient improvement.

Examination of HLA-DR4 as a severity marker for rheumatoid arthritis in Greek patients.

OBJECTIVES--Previous reports have shown that HLA-DR4 may be a severity marker for rheumatoid arthritis (RA) in patients of northern European origin. The aim of the present study was to investigate this relation in Greek patients with RA, as RA in Greece differs from the RA described previously on clinical, serological, and immunological grounds. METHODS--Eighty four patients were studied in whom HLA-DR typing was performed by restriction fragment length polymorphism and the subtypes of HLA-DR4 were determined by the polymerase chain reaction. The absence or presence of HLA-DR4 and its subtypes was correlated with the clinical and serological characteristics of the patients and with the side effects due to disease modifying drugs. RESULTS--Twenty one of the 84 (25%) patients with RA were DR4+. There was no difference between the DR4+ and DR4-patients with respect to duration of disease, severity of arthritis, functional grade, and joint erosion score. The DR4+ group were more likely to have side effects due to disease modifying drugs (43%) than DR4- patients (36%), but this difference was not statistically significant. DR4-patients had more extra-articular manifestations, including Sjögren's syndrome (47 v 19%). Analysis of the DR4 subtypes showed that Dw15 was the most common variant (9/21 patients; 43%). There was no statistical difference in the clinical manifestations among patients with different DR4 subtypes. The same was also true when the clinical picture was correlated with the 'shared RA epitope' (QKRAA/QRRAA/RRRAA), which is common to all HLA-DRB1 alleles positively associated with RA. CONCLUSIONS--These results suggest that HLA-DR4 is not a severity marker in Greek patients with RA and further indicate differences in the clinical expression of RA in Greece.     

Antiperinuclear factor as a prognostic marker in rheumatoid arthritis

OBJECTIVE: Antiperinuclear factor (APF) is an autoantibody detected in >50% of patients with rheumatoid arthritis (RA); it shows a specificity of roughly 90%. We investigated the possible role of APF as a prognostic marker in RA. METHODS: A series of 103 patients with RA who fulfilled the 1987 American College of Rheumatology criteria (88 women and 15 men; mean age 55.5 yrs, mean disease duration 9 yrs) were prospectively followed. Sixteen variables were assessed in each patient at inclusion and over a 3 year period. APF was determined by indirect immunofluorescence assay using human buccal mucosal cells as substrate. APF assays were done at entry and at the end of followup without knowledge of the clinical status of the patients. Mann-Whitney U, chi-squared tests, variance analysis, and kappa index were used for statistical analysis. RESULTS: Eighty of 103 patients completed followup. APF was detected in 40 of 80. At inclusion, APF correlated with the visual analog scale (VAS) of pain (p = 0.02). However, patients who showed APF positivity at entry had a less favorable course than APF negative individuals, as shown by a worse VAS of well being (p = 0.01), Ritchie index (p = 0.01), number of painful joints (p = 0.03), grip strength (p = 0.01), C-reactive protein (p = 0.04), and Health Assessment Questionnaire score (p = 0.03) at the end of the study. In addition, APF positive patients showed a worse radiological course (p = 0.03). CONCLUSION: Our results suggest APF is a possible marker of poor prognosis in RA.     

Amino-terminal pro-brain natriuretic peptide as a prognostic marker in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is associated with increased cardiovascular (CV) morbidity and mortality, of which amino-terminal pro-brain natriuretic peptide (NT-proBNP) is a predictor. The objective of the study was to investigate associations between NT-proBNP and age, gender, markers of inflammation, disease activity, and kidney function in RA patients, without co-morbidities potentially influencing NT-proBNP concentration. The study group consisted of 90 patients with RA, without clinically relevant coronary heart disease, hypertension, diabetes, advanced chronic kidney disease. The comprehensive assessment of clinical and laboratory parameters of inflammation, disease activity, and kidney function was performed. Plasma samples were frozen for NT-proBNP analysis. Carotid intima media thickness (cIMT) was determined by high-resolution B-mode ultrasonography. The mean NT-proBNP concentrations were significantly higher in a group of RA patients with high disease activity (DAS28 > 5.1) and in a group of patients with subclinical atherosclerosis diagnosed by cIMT ≥ 0.6 mm. In all RA patients, NT-proBNP correlated positively with the age, C-reactive protein, erythrocyte sedimentation rate, cIMT, tricipital skin fold and negatively with hand-grip strength, hemoglobin, red blood cell count, albumin. In the group of women with RA, we found significant positive correlation between NT-proBNP and cystatin-C. Also, patients with NT-proBNP level ≥ 100 pg/ml had significantly higher cystatin-C than those with lower NT-proBNP. NT-proBNP level, in RA patients without co-morbidities potentially influencing this level, is correlated with age, disease activity markers of inflammation, and subclinical renal impairment. It means that risk of CV disorders is higher in older patients with more active RA.     

Cytidine deaminase activity as a measure of acute inflammation in rheumatoid arthritis.

Cytidine deaminase (CD), a cytoplasmic enzyme, is thought to leak out of damaged cells and can be measured in fluids by a simple biochemical assay. This study has shown that serum CD activity is raised in rheumatoid arthritis (RA) compared with osteoarthritis (OA). Synovial fluid (SF) CD activity was always less than the corresponding serum activity (mean SF/serum ratio = 0.6) in OA but up to 22 times greater than the corresponding serum activity in RA (mean SF/serum ratio = 13.1), suggesting CD production in inflammatory joints. Evidence to support the SF neutrophil as a cell of CD origin is provided by the CD gradient running from cells to SF to synovium. The close correlation between SF CD activity and neutrophil count (r = 0.93) indicates that SF CD activity is an accurate measure of acute synovial inflammation. Weak correlation of serum CD activity with erythrocyte sedimentation rate (ESR) (r = 0.44) and C-reactive protein (CRP) (r = 0.49) implies that CD estimations supply different though related information about rheumatoid disease activity. We suggest that CD released from damaged neutrophils diffuses from all inflamed joints into the blood, so that serum CD activity may provide an integrated measure of joint inflammation more specific than traditional measures such as the ESR.     

Assessment of endothelial function as a marker of cardiovascular risk in patients with rheumatoid arthritis

The endothelium is a major regulator of cardiovascular function and maintains an atheroprotective role through several mechanisms, including vasodilatation, inhibition of platelet aggregation, having anticoagulant and profibrinolytic effects, and having an anti‐inflammatory effect. Early changes in the normal functioning of the endothelium are key initiating factors in the development and progression of atherosclerosis. These changes are present well before the presentation of clinical symptoms. Thus, researchers have focused much attention on developing methods for reliable non‐invasive testing of endothelial function to allow early detection and monitoring and progression of subclinical atherosclerosis. To date, there is a wide range of methods in use to assess endothelial function, each with its own advantages and limitations. Ideally, the tests should be non‐invasive to allow repeated measurements and be applicable in normal healthy subjects and also in children. Given the wide range of regulatory functions of the endothelium, it is not surprising that there is no single measure of endothelial function that provides all the necessary information regarding vascular integrity in different vascular beds. Therefore, a combination of tests examining different components of the vascular system is more appropriate. Since patients with rheumatoid arthritis have increased mortality due to cardiovascular disease, assessment of endothelial function could prove to be useful tools in the identification and monitoring of cardiovascular risk. The purpose of this review is to give a brief overview of some of the commonly used techniques for assessment of endothelial function, and in particular on those that have been used in studies of patients with rheumatoid arthritis.     

Plasma monocyte chemoattractant protein 1 is a marker for joint inflammation in rheumatoid arthritis

OBJECTIVE: Monocyte chemoattractant protein 1 (MCP-1) level in plasma is described as a marker for joint inflammation in rheumatoid arthritis (RA). METHODS: MCP-1 in plasma and synovial fluid (SF) was quantified by ELISA in 36 RA patients with synovitis of the knee at Day 1 and 30. Disease activity was assessed by the swollen joint count, Ritchie Articular Index (RAI), global assessment, pain on visual analog scale, Health Assessment Questionnaire, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). RESULTS: By linear regression analysis plasma MCP-1 levels correlated significantly with the swollen joint count (Day 1: R = 0.47, p = 0.005; Day 30: R = 0.53, p < 0.001) and the RAI (Day 1: R = 0.37, p = 0.03; Day 30: R = 0.41, p = 0.01). The correlations of swollen joint count and RAI with ESR and CRP were significant only on Day 30 for the ESR (R = 0.40, p = 0.02). No association was found between plasma MCP-1 levels and the ESR/CRP levels. MCP-1 levels in plasma in RA patients were elevated compared to controls (p < 0.001) and MCP-I levels in SF were higher than in plasma (p < 0.001). No correlation was found between SF MCP-1 levels and in vitro migration of mononuclear cells towards SF. MCP-1 appears to participate in the disease process in RA, and plasma MCP-1 may be useful in monitoring joint inflammation.     

Serum alpha 1 antichymotrypsin concentration as a marker of disease activity in rheumatoid arthritis.

Serum alpha 1 antichymotrypsin (alpha 1ACT), C reactive protein (CRP), orosomucoid, and erythrocyte sedimentation rate (ESR) were measured sequentially in 20 patients with rheumatoid arthritis (RA) treated with gold or penicillamine. Pain score, morning stiffness, grip strength, and articular index were measured and a Mallya score calculated. Based on a total of 148 sets of observations, significant correlations were found between alpha 1ACT and other variables (p less than 0.001 except morning stiffness at p less than 0.05). The actual correlation coefficients indicated a closer association with the other laboratory tests, CRP (0.62), orosomucoid (0.69), and ESR (0.61), than with clinical measurements: pain score (0.38), articular index (0.41), grip strength (-0.3), morning stiffness (0.19), and Mallya score (0.5). Sequential data on individual patients showed differing patterns of change in the variables indicating the importance of measuring more than one acute phase protein (APP), especially when CRP is inappropriately low. Serum alpha 1ACT concentration does reflect disease activity in RA. Its potential advantages are discussed.     

Formal education as a marker for increased mortality and morbidity in rheumatoid arthritis

Increased mortality and morbidity was seen in association with lower formal educational levels in 75 rheumatoid arthritis (RA) patients over 9 years. Nine of the 20 patients with 8 or fewer years of education had died, compared to 10 of 34 with 9-12 years of education, and only one of 21 with more than 12 years of education. Among survivors with functional capacity data available from baseline and 9 year review, declines greater than 20% were seen in 8 of 10, 13 of 21, and 9 of 19 patients in the three education categories. Overall, 79% of grade-school educated, 43% of high-school educated, and 20% of college-educated patients had either died or declined more than 50% in functional capacity. Patients of different formal educational levels were similar at baseline in age, duration of disease, measures of functional capacity, number of involved hand joints, number of severe radiographic changes, use of gold, oral corticosteroids or other therapies, and associations between formal educational level and disease course are not explained by these variables. Formal educational level appears a simple quantitative marker which identifies a surrogate or composite variable associated with increased mortality and morbidity in RA.     

Airways disease in rheumatoid arthritis patients. One element of a general exocrine dysfunction

Airflow limitation is a frequent finding in patients with rheumatic diseases. We have previously suggested that it is associated with autoimmune exocrinopathy in Sj?gren's syndrome. To compare clinical features of patients with and without airways dysfunction and to further test the hypothesis of a link between airways disease and exocrinopathy, we prospectively studied 2 groups of 15 lifetime nonsmoker female patients with seropositive rheumatoid arthritis (RA). The 2 groups were similar in their clinical and immunologic features, but differed in terms of airways function. Salivary, lacrimal, and sweat gland dysfunction were significantly more prevalent or severe in the group with airways disease. Antinuclear antibodies were also more prominent in the patients with airways disease, but antibodies against RNP, SS-A, SS-B, and double-stranded DNA were not present in these patients. HLA-DR4 was found in 80% of the RA patients with airways disease and in 57% of those without airways disease. HLA-B8 and DR3 were equivalently distributed in both groups. This prospective study further documents the existence of small airways disease in RA and supports the view that autoimmune exocrinopathy predisposes to its expression.     

High sensitivity C-reactive protein as a disease activity marker in rheumatoid arthritis

OBJECTIVE: To elucidate the potential contribution of high sensitivity C-reactive protein (hs-CRP) testing in the assessment of disease activity in rheumatoid arthritis (RA). METHODS: We recorded clinical and psychological variables, the hs-CRP, and erythrocyte sedimentation rate (ESR) in 146 consecutive patients with RA. We analyzed the associations between the ESR and hs-CRP versus the other recorded variables. RESULTS: The median (interquartile range) ESR (mm/h) and hs-CRP (mg/l) were 15 (7-36) and 5 (2.3-13.9), respectively. Thirty-two (22%) patients had an hs-CRP < 2 mg/l, 61 (42%) an hs-CRP of 2-8 mg/l and 53 (36%) an hs-CRP > 8 mg/l. In patients with an hs-CRP of 2-8 mg/l, the swollen joint counts and the physician disease activity scales were higher, and remission rates were lower than in patients with an hs-CRP of < 2 mg/l. The hs-CRP was consistently more closely associated with disease activity, depression, and helplessness than was the ESR. CONCLUSION: High sensitivity CRP testing reveals systemic inflammation that is generally not detectable with routine CRP assays and that is associated with disease activity in RA.     

Blocking the receptor for C5a in patients with rheumatoid arthritis does not reduce synovial inflammation

OBJECTIVES: All complement pathways lead to the formation of C5a, which is believed to contribute to the influx and activation of C5a-receptor (C5aR) bearing cells into the joints of patients with rheumatoid arthritis (RA). Studies in animal models of RA have suggested therapeutic potential of C5aR blockade. In this study, we examined the effects of the C5aR blockade on synovial inflammation in RA patients. METHODS: We performed a double-blind, placebo-controlled study using an orally administered C5aR-antagonist. Twenty-one patients with active RA were randomized 2:1 to treatment with a C5aR-antagonist AcF- (OpdChaWR) (PMX53) vs placebo for 28 days. Serum concentrations of PMX53 were determined. Synovial tissue was obtained at baseline and after 28 days of treatment for pharmacodynamic analysis using immunohistochemistry and digital image analysis. RESULTS: All patients completed the study. Areas under the curve (AUCs) of PMX53 in patients' blood samples showed a mean of 40.8 nmol h/l. There was neither decrease in cell infiltration, nor changes in key biomarkers associated with clinical efficacy after active treatment. In addition, there was no trend towards clinical improvement in the C5aR-antagonist-treated group compared with placebo nor was there a correlation between the AUC and clinical response. CONCLUSIONS: Treatment with PMX53 did not result in a reduction of synovial inflammation despite reaching serum levels of PMX53 that block C5aR-mediated cell activation in vitro. The data suggest that C5aR blockade does not result in reduced synovial inflammation in RA patients.     

Formal education level as a significant marker of clinical status in rheumatoid arthritis

Clinical status was assessed in 385 patients with rheumatoid arthritis, according to erythrocyte sedimentation rate, joint count, grip strength, walking time, and other quantitative measures. All measures indicated substantially poorer clinical status in patients who did not complete high school, compared with those who had completed high school. In general, the poorest results were seen in patients with only a grade school education. Progressively better results were seen in patients with some high school education, high school graduates, and patients with some college education. No differences in clinical status were seen among patients who had attended college, graduated from college, or had postgraduate education. Although patients seen at the Veterans Administration Medical Center had lower levels of formal education than those seen at a university clinic and private practices, trends in clinical status according to formal education level were similar in all three clinical settings. Differences in clinical status according to formal education level are not explained by age, sex, duration of disease, clinical setting, or multiple comparisons. Formal education level may identify an important marker of clinical status in rheumatoid arthritis.