Untreated RA Research Articles

T-Cell Subsets in Rheumatoid Arthritis Patients on Long-Term Anti-TNF or IL-6 Receptor Blocker Therapy.

Data on the impact of biological therapies on the T-cell phenotype in rheumatoid arthritis are limited. Here, we prospectively measured the percentages of 15 circulating T-cell subtypes using flow cytometry. We obtained transversal and longitudinal data in 30 anti-TNF responders, 19 secondary anti-TNF nonresponders, and 43 IL-6R antagonist responders, before, 8 weeks and at least 6 months after biological therapy. Untreated RA patients and healthy controls were also included. The important findings are the following: (1) the proportion of regulatory T-cells (Tregs) which are decreased in untreated RA patients becomes normal in all long-term-treated groups; (2) in anti-TNF responders as well as in nonresponders, the frequencies of naïve CD4+ and CD8+ cells are lower, whereas those of proinflammatory Th1, Th2, and Th17 cells and HLA-DR+-activated cells are higher than those in untreated RA or healthy controls; (3) in IL-6R responders, Th1 proportion is decreased, while that of Th2 and Th17 is increased as compared to that in anti-TNF-treated patients and controls; (4) pending confirmation, a CD4CD69 ratio < 2.43 at baseline, could be useful to predict a good therapeutic response to anti-TNF therapy. This study provides comprehensive information regarding the long-term impacts of those biological therapies on the ecotaxis of T-cells in RA. The ClinicalTrials.gov registration number of our study is NCT03266822.

Higher expression of TNFα-induced genes in the synovium of patients with early rheumatoid arthritis correlates with disease activity, and predicts absence of response to first line therapy.

BackgroundIL6-related T cell activation and TNFα-dependent cell proliferation are major targets of therapy in the RA synovium. We investigated whether expression of these pathways in RA synovial biopsies is associated with disease activity and response to therapy.MethodCorrelation and gene set enrichment studies were performed using gene expression profiles from RA synovial biopsies. Immunostaining experiments of GADD45B and PDE4D were performed on independent additional sets of early untreated RA samples, obtained in two different centers by needle-arthroscopy or US-guided biopsies.ResultsIn 65 RA synovial biopsies, transcripts correlating with disease activity were strongly enriched in TNFα-induced genes. Out of the individual variables used in disease-activity scores, tender joint count, swollen joint count and physician’s global assessment, but not CRP or patient’s global assessment displayed a similar correlation with the expression of TNFα-dependent genes. In addition, TNFα-induced genes were also significantly enriched in transcripts over-expressed in synovial biopsy samples obtained from poor-responders to methotrexate or tocilizumab, prior to initiation of therapy.GADD45B (induced by TNFα in monocytes) and PDE4D (induced by TNFα in FLS) immunostaining was significantly higher in overall poor-responders to therapy in 46 independent baseline samples obtained from early untreated RA patients prior to initiation of therapy. GADD45B (but not PDE4D) immunostaining was significantly higher in the sub-group of patients with poor-response to methotrexate therapy, and this was confirmed in another population of methotrexate-treated patients.ConclusionHigher expression of TNFα-induced transcripts in early RA synovitis is associated with higher disease activity, and predicts poor response to first-line therapy. That over-expression of TNFα-induced genes predicts poor-response to therapy regardless of the drug administered, indicates that this molecular signature is associated with disease severity, rather than with specific pathways of escape to therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-0919-z) contains supplementary material, which is available to authorized users.

Some Diagnostic Aspect on Abnormal Nitric Oxide Metabolism and Some Pharmacological Aspects of the most used Drugs in Rheumatoid Arthritis

Introduction: To evaluate the diagnostic test for Assymetric Dimethyl Arginine (ADMA), rheumatoid factor (RF), C-reactive protein (CRP), Disease Activity Score with 28 joint ( DAS 28 index ), and to define the effect of untreated rheumatoid arthritis on endothelial function. In order to determine whether ADMA changes depending on the disease evolution, ADMA was used as an indicator for endothelial dysfunction in subclinical atherosclerosis Methods: Using a ELISA technology of DLD-Diagnostika-GMBH for detection of ADMA, the samples of serum and urine have been examined in 70 participants (35 RA who were not treated, 35 healthy controls). RF was defined with the test for agglutination (Latex RF test) in the same participants. Results: Out of 35 examined patients with RA, RF appeared in 18 patients (sensitivity of the test 48.57 %), while ADMA is positive in 20 patients (sensitivity of the test 57.14 %) in the same group. In 23 of the 35 examined patients with RA, we found presence of anti-citrulinated peptide antibodies (anti-CCP2) from the second generation (anti-CCP 2 antibodies ) (sensitivity of the test 65.71%). There is association between ADMA and anti-citrulated peptide antibodies (anti-CCP2) from the second generation in early RA (p<0.05). Conclusion: ADMA higher sensitivity than RF in the detection of asymptomatic subclinical lesions in untreated RA. ADMA has equal sensitivity and specificity from RF in untreated RA.

Effect of mesenchymal precursor cells on the systemic inflammatory response and endothelial dysfunction in an ovine model of collagen-induced arthritis.

Background and AimMesenchymal precursor cells (MPC) are reported to possess immunomodulatory properties that may prove beneficial in autoimmune and other inflammatory conditions. However, their mechanism of action is poorly understood. A collagen-induced arthritis model has been previously developed which demonstrates local joint inflammation and systemic inflammatory changes. These include not only increased levels of inflammatory markers, but also vascular endothelial cell dysfunction, characterised by reduced endothelium-dependent vasodilation. This study aimed to characterise the changes in systemic inflammatory markers and endothelial function following the intravenous administration of MPC, in the ovine model.MethodsArthritis was induced in sixteen adult sheep by administration of bovine type II collagen into the hock joint following initial sensitisation. After 24h, sheep were administered either 150 million allogeneic ovine MPCs intravenously, or saline only. Fibrinogen and serum amyloid-A were measured in plasma to assess systemic inflammation, along with pro-inflammatory and anti-inflammatory cytokines. Animals were necropsied two weeks following arthritis induction. Coronary and digital arterial segments were mounted in a Mulvaney-Halpern wire myograph. The relaxant response to endothelium-dependent and endothelium-independent vasodilators was used to assess endothelial dysfunction.Results and ConclusionArthritic sheep treated with MPC demonstrated a marked spike in plasma IL-10, 24h following MPC administration. They also showed significantly reduced plasma levels of the inflammatory markers, fibrinogen and serum amyloid A, and increased HDL. Coronary arteries from RA sheep treated with MPCs demonstrated a significantly greater maximal relaxation to bradykinin when compared to untreated RA sheep (253.6 ± 17.1% of pre-contracted tone vs. 182.3 ± 27.3% in controls), and digital arteries also demonstrated greater endothelium-dependent vasodilation. This study demonstrated that MPCs given intravenously are able to attenuate systemic inflammatory changes associated with a monoarthritis, including the development of endothelial dysfunction.

Some Diagnostic Aspect with Overall Clinical Expression of Asymmetric Dimethylarginine as an Hallmark for Evaluation of Subclinic Athrosclerosis in Patients with Rheumatoid Arthritis with Aspect on Abnormal Nitric Oxid Metabolism and Some Pharmacological Aspects of the Most Used Drugs in RA

Introduction: To evaluate the diagnostic test for Asymmetric Dimethyl Arginine (ADMA), rheumatoid factor (RF), C-reactive protein (CRP), Disease Activity Score with 28 joint (DAS 28 index), and to define the effect of untreated rheumatoid arthritis on endothelial function. In order to determine whether ADMA changes depending on the disease evolution, ADMA was used as an indicator for endothelial dysfunction in subclinical atherosclerosis. Methods: Using an ELISA technology of DLD-Diagnostic-GMBH for detection of ADMA, the samples of serum and urine have been examined in 70 participants (35 RA who were not treated, 35 healthy controls). RF was defined with the test for agglutination (Latex RF test) in the same participants. Results: Out of 35 examined patients with RA, RF appeared in 18 patients (sensitivity of the test 48.57%), while ADMA is positive in 20 patients (sensitivity of the test 57.14%) in the same group. In 23 of the 35 examined patients with RA, we found presence of anti-circulated peptide antibodies (anti-CCP2) from the second generation (anti- CCP2 antibodies) (sensitivity of the test 65.71%). There is association between ADMA and anti-circulated peptide antibodies (anti-CCP2) from the second generation in early RA (p<0.05). Conclusion: ADMA higher sensitivity than RF in the detection of asymptomatic subclinical lesions in untreated RA. ADMA has equal sensitivity and specificity from RF in untreated RA.

Cardiovascular risk in rheumatoid arthritis: recent advances in the understanding of the pivotal role of inflammation, risk predictors and the impact of treatment.

Risk of cardiovascular (CV) disease is increased among RA patients. High inflammatory burden associated with RA appears to be a key driver of the increased cardiovascular risk. Inflammation is linked with accelerated atherosclerosis and associated with a paradoxical inversion of the relationship between CV risk and lipid levels in patients with untreated RA, recently coined the lipid paradox. Furthermore, the inflammatory burden is also associated with qualitative as well as quantitative changes in lipoproteins, with the anti-inflammatory and atheroprotective roles associated with high-density lipoprotein cholesterol significantly altered. RA therapies can increase lipid levels, which may reflect the normalization of lipids due to their inflammatory-dampening effects. However, these confounding influences of inflammation and RA therapies on lipid profiles pose challenges for assessing CV risk in RA patients and interpretation of traditional CV risk scores. In this review we examine the relationship between the increased inflammatory burden in RA and CV risk, exploring how inflammation influences lipid profiles, the impact of RA therapies and strategies for identifying and monitoring CV risk in RA patients aimed at improving CV outcomes.

THU0496 B-Cell Subpopulations Differ in Rheumatoid Arthritis Patients with and without Autoantibodies

BackgroundRheumatoid arthritis (RA) is a common, destructive and non-curable autoimmune disease that affects approximately 0.5-1% of the population of the Western world. The importance of B cells in RA has...

Prevotella copri associated with new-onset untreated RA

Prevotella copri associated with new-onset untreated RA

Determination of the Diagnostic Values of Asymmetric Dimethylarginine as an Indicator for Evaluation of the Endothelial Dysfunction in Patients with Rheumatoid Arthritis

Introduction. To compare the diagnostic values of laboratory variables, to present evaluations of the diagnostic test for asymmetric dimethyl arginine (ADMA), rheumatoid factor (RF), C-reactive protein (CRP), and DAS28 index, and to define the effect of untreated rheumatoid arthritis on endothelial function. In order to determine whether ADMA changes depending on the disease evolution, ADMA was used as an indicator for endothelial dysfunction. Methods. Using an ELISA technology of DLD-Diagnostika-GMBH for the detection of ADMA, the samples of serum and urine have been examined in 70 participants (35 RA who were not treated, 35 healthy controls). RF was defined with the test for agglutination (Latex RF test) in the same participants. Results. Out of 35 examined patients with RA, RF appeared in 17 patients (sensitivity of the test, 51.42%). In 20 of the 35 examined patients with RA, we found the presence of ADMA (sensitivity of the test, 57.14%). Anti-CCP antibody was present in 24 examined patients with RA (sensitivity of the test, 68.57%). Conclusion. ADMA has equal or very similar sensitivity and specificity to RF in untreated RA (sensitivity of 57.14% versus 48.57%, specificity of 88.57% versus 91.42%) in the detection of asymptomatic endothelial dysfunction in untreated RA.

The impact of allergic rhinitis on symptoms, and quality of life using the new criterion of ARIA severity classification

Allergic rhinitis (AR) is a common disease with major socieconomic burden and a significant impact on quality of life. The objective of the study was to assess the impact of AR severity, using the modified ARIA (m-ARIA) severity criterion in order to discriminate among moderate and severe AR, in symptoms and quality of life assessed with the questionnaire ESPRINT-15. The specific quality of life questionnaire (ESPRINT-15) was applied in over thousand untreated RA patients. Severity was evaluated by the m-ARIA classification, which categorizes AR as mild, moderate, and severe. Nasal symptoms were evaluated by using categorized (none, low, middle, and high) Total Four Symptom Score (T4SS). Using the m-ARIA severity classification, significant differences in quality of life, both global score and specific domains, and categorized T4SS were found among the AR severity groups. Modified ARIA severity classification in mild, moderate, and severe allergic rhinitis clearly discriminates the impact of AR in all domains of quality of life and categorized symptom`s score.

The impact of allergic rhinitis on symptoms, and quality of life using the new criterion of ARIA severity classification

Introduction: Allergic rhinitis (AR) is a common disease with major socieconomic burden and a significant impact on quality of life. Objective: The objective of the study was to assess the impact of AR severity, using the modified ARIA (m-ARIA) severity criterion in order to discriminate among moderate and severe AR, in symptoms and quality of life assessed with the questionnaire ESPRINT-15. Methods: The specific quality of life questionnaire (ESPRINT-15) was applied in over thousand untreated RA patients. Severity was evaluated by the m-ARIA classification, which categorizes AR as mild, moderate, and severe. Nasal symptoms were evaluated by using categorized (none, low, middle, and high) Total Four Symptom Score (T4SS). Results: Using the m-ARIA severity classification, significant differences in quality of life, both global score and specific domains, and categorized T4SS were found among the AR severity groups. Conclusion: Modified ARIA severity classification in mild, moderate, and severe allergic rhinitis clearly discriminates the impact of AR in all domains of quality of life and categorized symptom`s score.

Subclinical remodelling of draining lymph node structure in early and established rheumatoid arthritis assessed by power Doppler ultrasonography

To investigate the suitability of power Doppler ultrasonography (PD-US) for the assessment of lymph node (LN) status in RA, evaluating the existence of structural and dynamic modifications in well-characterized stages of the disease. Ten patients with active disease and five patients in clinical remission underwent complete clinical and PD-US examination of hands, wrists, axillary and cervical LNs on the same day. Synovitis and PD were graded 0-3. LN assessment included maximum short axis, cortical hypertrophy (CH) and PD signal distribution. All patients with active disease were re-evaluated prospectively 3 months after initiation of therapy. PD-US signs of axillary LN remodelling were observed in 7 out of 10 patients with active disease despite the absence of clinical lymphoadenopathy. Subclinical alterations were detected in both early untreated RA and in established disease. Characteristic structural changes consisted of hypertrophy of the LN cortex and PD signal amplification in cortical and hilar regions. Cervical LNs in active disease and axillary LNs in clinical remission were unaffected. LN PD amplification returned to normal ranges in patients with baseline alterations re-evaluated 3 months after therapy with TNF-α blocking agents and/or MTX. Draining LNs in RA are subjected to subclinical intra-parenchymal changes and vascular flow modulation detectable by PD-US. Sonographic signs of LN involvement associate with disease activity and are reversible upon treatment. These data point at LN reactivity as a dynamic component of RA inflammatory cascade and an attractive platform to be explored in prognostic and response to therapy evaluations.

Diurnal variation of connective tissue metabolites in early and long-standing rheumatoid arthritis and in healthy individuals

Objective:To study the circadian variability of circulating connective tissue metabolites in patients with very early (VERA) and long-standing rheumatoid arthritis (LRA) and in healthy control individuals.Methods:Eleven patients with newly diagnosed, untreated RA, disease duration < 6 months, and 10 patients with LRA were included, together with 16 healthy control subjects. Seven blood samples were drawn serially from each participant at 3-hourly intervals from 10.00–22.00 h, fasting at 07.00 h the following day and finally at 10.00 h. Cartilage oligomeric matrix protein (COMP) and hyaluronan (HYA) were quantified by enzyme-linked immunosorbent assay (ELISA) and the N-terminal propeptide of collagen type III (PIIINP) was determined by radioimmunoassay (RIA).Results: The two RA subsets did not differ with respect to age, gender distribution, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), immunoglobulin M rheumatoid factor (IgM-RF) status, global health status and pain. Healthy controls were younger than both VERA and LRA patients. At baseline, PIIINP, HYA, and COMP were increased significantly in both RA cohorts compared with controls. No circadian rhythmicity was recorded with respect to HYA and PIIINP. By contrast, COMP was decreased at 07.00 h in all three study groups; this decline was particularly prominent in LRA.Conclusion:Within-day changes of PIIINP, HYA, and COMP are qualitatively similar in RA at different stages and in healthy individuals, indicating that the connective tissue responses to rhythmic physiological signals are not abolished by disease-modifying anti-rheumatic drug (DMARD) therapy. Serum for measurement of HYA and COMP should be collected between 10.00 and 20.00 h.

Evidence for Improved Neuropharmacological Efficacy and Decreased Neurotoxicity in Mice with Traditional Processing ofRhizoma Arisaematis

Rhizoma Arisaematis (RA, the rhizome of Pinellia pedatisecta Schott) is a traditional Chinese medicine commonly used in the treatment of convulsions, inflammation, and cancer. Despite the fact that it has been used for more than 2000 years, the pharmacological and toxic effects of traditionally processed products of RA are still unclear. In this study, we attempted to investigate the effects exerted by untreated crude RA and different preparations of RA treated with alumen in combination with ginger juice (Zhinanxing) or bile juice (Dannanxing) in ICR mice. The results showed that both the Zhinanxing and Dannanxing water extracts exerted significantly increased sedative effects, as indicated by the inhibitory effects on ambulatory distances, jumps, vertical-plane entries, and prolonged pentobarbital-induced sleeping time. The extracts also exerted significantly increased analgesic effects (increase of tail flick latency in nociceptive testing) in mice than did the unprocessed crude RA after oral administration for one to three days, and effects persisted 18 days after the cessation of treatment. By contrast, the toxic effects, such as an increase in stereotype-1 episodes of locomotor activities and reduction of the retention time on a rotating rod (motor equilibrium dysfunction), were observed only in mice treated with the unprocessed crude RA for three consecutive days, and effects persisted for 18 days after the cessation of treatment. These neurotoxic effects were accompanied by an increase in plasma lipid peroxidation (LPO), decrease in whole blood nitric oxide (NO(x)) levels, and inhibition of Na(+)/K(+)-ATPase activities in membrane fractions of erythrocytes and in the cerebral cortex. In conclusion, these findings provide scientific evidence that the processed RA indeed possesses not only enhanced neuropharmacological efficacy but also reduced neurotoxic effects as compared to the unprocessed crude RA. The signaling of NO(x)/oxidative stress/Na(+)-K(+)- ATPase activities played a role, at least in part, in the underlying mechanisms of neurotoxic effects induced by the crude RA.

Comparative study of serum and synovial fluid interleukin-11 levels in patients with various arthritides

Objective: To determine the levels of serum and synovial fluid (SF) interleukin (IL)-11 in patients with various arthritides and estimate the contribution of IL-11 to acute phase response (APR). Design and methods: Serum and SF IL-11 were measured by ELISA in patients with rheumatoid arthritis (RA, n = 31), seronegative spondyloarthritis (SSA, n = 23), gout (GT, n = 14) and osteoarthritis (OA, n = 20) and were correlated with ESR and acute phase proteins as well as with cytokines IL-1α, IL-1β, IL-6, and TNFα. Results: IL-11 was detected in both serum and SF in each group, with IL-11 being statistically higher in SF than serum in all groups, suggesting reduced catabolism or increased synthesis of IL-11 intra-articularly. Median SF IL-11 levels were higher in OA patients than in other groups and in the treated than in the untreated RA subgroup. Moreover, serum and SF IL-11 were correlated significantly with each other, and moderately with the other cytokines examined in RA, SSA, and GT, but not in OA patients, while a significant negative correlation was found with a few of the inflammatory markers examined in each group. Conclusions: Our findings provide evidence of extensive intra-articular expression of IL-11 in arthritides, especially in OA and treated RA patients, suggesting a protective role for IL-11 in joints, probably through the induction of tissue inhibitor of metalloproteinases.

Effect of sulphasalazine on gastrointestinal microflora and on mucosal heat shock protein expression in patients with rheumatoid arthritis.

This study was performed in order to elucidate a possible association between mucosal heat shock protein expression, the gastrointestinal microflora and disease activity in 17 patients with RA before and after 16 weeks of sulphasalazine (SASP) treatment. The duodenal-jejunal mucosal binding of the monoclonal antibody ML30, recognizing the 65 kDa heat shock protein of mycobacteria, was increased (P = 0.048) in the untreated RA patients compared to controls, but did not correlate to disease, activity or microflora and was not altered by SASP therapy. There was no convincing evidence for bacterial overgrowth in the jejunum and the faecal microflora was normal. SASP treatment altered the faecal microflora, with significant reductions of the total aerobic bacteria, Escherichia coli and Bacteroides, and increased numbers of Bacillus. SASP had only minor effects on the jejunal microflora. A high carriage frequency of Candida albicans was found in saliva and the counts correlated negatively with the unstimulated whole salivary secretion rate. These results suggest that the gut may be involved in the aetiopathogenesis of RA but do not substantiate the hypothesis that the anti-rheumatic effects of SASP are mediated via its anti-microbial properties. However, the possibility that a micro-organism, not detected in this study, may be of crucial importance in RA, cannot be ruled out.