Special Issue:
Challenges and Opportunities in Rheumatoid Arthritis
Leena Äyräväinen, DDS, PhD
Post-doc researcher, Department of Oral and Maxillofacial Diseases, University of Helsinki.
Anna Maria Heikkinen, DDS, PhD
Professor, Faculty of Medicine and Health Technology, University of Tampere, Wellbeing Services County of Pirkanmaa, Oral Health Care.
Jukka H Meurman, MD, PhD
Professor, Department of Oral and Maxillofacial Diseases, University of Helsinki.
Abstract
This is a narrative review describing how oral infections and diseases associate with rheumatoid arthritis. From the voluminous oral microbiom, bacteria can get access to circulation through inflamed periodontal tissue, oral mucosa, and carious teeth. This results in upregulation of a number of chemokines and cytokines that often cause chronic, subclinical systemic inflammation with consequent organ pathology. The periodontal pathogen Porphyromonas gingivalis was observed to cause citrullination of proteins that play a role in the development of arthritis by generating of specific autoantibodies such as anti-citrullinated peptide antibody. These migrate and form immune complexes at the synovial membrane of joints. In general, patients with rheumatoid arthritis should have a healthy mouth. Dry mouth is a symptom seen among many patients with rheumatic diseases, also rheumatoid arthritis. Because saliva is one of the principal defense factors of the mouth, hyposalivation renders the patient liable to oral diseases. Consequently, the patients must drink enough daily and use saliva substitutes when necessary, and, above all, maintain good oral hygiene daily. In rheumatoid arthritis, manual dexterity may be impaired, however, causing cleaning the teeth difficult. Hence, patients with rheumatic diseases like rheumatoid arthritis need counseling and individual oral health care instructions by oral health care professionals for implementation at home. An electric toothbrush should be recommended. Regular oral health examinations by dentists are needed more often than among the healthy.
Veronica Mezhov, Emma Guymer, Sudha Raghunath, Rangi Kandane-Rathnayake, Michelle Leech, Eric Morand & Geoffrey Littlejohn
Abstract
Objective: To assess the impact of central sensitization as measured by the ‘Central Sensitivity Score’ on rheumatoid arthritis disease activity change.
Methods: This was a prospective cohort study of rheumatoid arthritis patients receiving routine clinical care. At baseline, participants had assessment of rheumatoid arthritis disease activity from a 3-variable Disease Activity Score with 28 Joint Count Erythrocyte Sedimentation Rate, symptoms of central sensitization (from central sensitivity score, the numerical score derived from the 2016 American College of Rheumatology Fibromyalgia diagnostic criteria), demographic and clinical variables. A follow-up 3-variable Disease Activity Score with 28 Joint Count Erythrocyte Sedimentation Rate was collected on the next routine clinic appointment (median 3 months). The association of central sensitivity score and change in rheumatoid arthritis disease activity was assessed using a multivariate linear regression analysis.
Results: Data were obtained from 82 participants. The median baseline 3-variable Disease Activity Score with 28 Joint Count Erythrocyte Sedimentation Rate across the cohort was 2.44. On multivariate linear regression a higher baseline central sensitivity score independently predicted improvement in 3-variable Disease Activity Score with 28 Joint Count Erythrocyte Sedimentation Rate (regression coefficient=-0.02, 95% CI [-0.08 to -0.01]). A higher C-Reactive Protein was also an independent predictor of improvement in the 3-variable Disease Activity Score with 28 Joint Count Erythrocyte Sedimentation Rate (regression coefficient -0.02, 95% CI [-0.04 to 0.01]). Exposure to a higher number of biologics predicted worsening in 3-variable Disease Activity Score with 28 Joint Count Erythrocyte Sedimentation Rate (regression coefficient=0.28, 95% CI [0.08 to 0.48]).
Conclusion: In this closely monitored cohort with relatively well-controlled disease, a higher baseline central sensitivity score was predictive of a small but not clinically meaningful change in objective rheumatoid arthritis disease activity.
Azad Mohammad, DrPH
Institute for Health and the Environment, University at Albany, Rensselaer, NY 121144
David O. Carpenter, MD
Institute for Health and the Environment, University at Albany, Rensselaer, NY 121144
Abstract
Rheumatoid arthritis is an autoimmune disease, while osteoarthritis is presumed to be a disease due to wear and tear causing damage to joints. Some environmental exposures, such as smoking, air pollution and possibly persistent organic pollutants, are known to increase the risk of both. We have utilized the National Health and Nutrition Examination Survey (NHANES) data to determine associations between self-reported prevalence of any form of arthritis, rheumatoid and osteoarthritis and various polychlorinated biphenyl (PCB) congeners, several chlorinated pesticides and 2.3,7,8-tetrachloro-dibenzo-dioxin (TCDD). We find that there is a statistically significant association between serum PCB levels of more highly chlorinated PCB congeners and both types of arthritis. The associations are stronger with rheumatoid arthritis than with osteoarthritis, and stronger in women than in men.
George A Karpouzas, MD
Division of Rheumatology, Harbor-UCLA Medical Center and Lundquist Institute for Biomedical Innovation, Torrance, CA, USA
Elizabeth Hernandez, MA
Division of Rheumatology, Harbor-UCLA Medical Center and Lundquist Institute for Biomedical Innovation, Torrance, CA, USA
Matthew J Budoff, MD
Division of Cardiology, Harbor-UCLA Medical Center and Lundquist Institute for Biomedical Innovation, Torrance, CA, USA
Sarah R Ormseth, PhD
Division of Rheumatology, Harbor-UCLA Medical Center and Lundquist Institute for Biomedical Innovation, Torrance, CA, USA
Abstract
Objectives. Underweight patients with rheumatoid arthritis incur greater total and cardiovascular mortality compared to overweight or obese. We explored whether obesity confounded cardiovascular risk estimates and the potential utility of noninvasive coronary atherosclerosis assessment and cardiac damage biomarkers in optimizing risk prediction in obese patients with rheumatoid arthritis.
Methods. We evaluated 150 participants undergoing screening atherosclerosis evaluation with coronary computed tomography angiography and follow-up over 6.0±2.4 years. Framingham 2008 modified general cardiovascular risk score was computed at baseline. Obesity was defined as waist circumference >88 cm in females and >102 cm in males. Serum highly-sensitive cardiac troponin I (hs-cTnI) and leptin were measured at baseline.
Results. An interaction between the Framingham risk score and obesity on cardiovascular risk was observed (p=0.032); lower estimates were seen in obese (area under the curve-AUC 0.660, 95% CI 0.487-0.832) vs. non-obese patients (AUC 0.952, 95% CI 0.897-1.007, p=0.002). Likewise, risk estimates were inferior in patients with high (>22.1 ng/ml) vs. low leptin (AUC 0.618, 95% CI 0.393-0.842 vs. 0.874, 95% CI 0.772-0.976, p=0.042). In obese patients, sequential addition of the top highly-sensitive cardiac troponin I tertile values and extensive atherosclerotic plaque (>5 segments) information to a base model including the Framingham risk score alone significantly improved risk estimates, based on changes in net reclassification index (1.093 95% CI 0.517-1.574), integrated discrimination improvement (0.188, 95% CI 0.060-0.526), and AUC (0.179, 95% CI 0.058-0.378, p=0.02). The final, combined model accurately predicted 83.9% of incident cardiovascular events.
Conclusion. Obesity attenuated cardiovascular risk estimate accuracy in patients with rheumatoid arthritis. Risk optimization employing non-invasive assessment of coronary atherosclerosis burden and serum cardiac damage biomarkers may warrant further study.
Masao Tanaka
Department of Advanced Medicine for Rheumatic Diseases, Graduate School of Medicine, Kyoto University
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic joint inflammation and destruction. The affected synovium becomes the basis of the inflammatory milieu by recruiting immune cells including T cells, B cells, monocytes, macrophages and granulocytes etc., and activates osteoclasts leading to joint destruction and dysfunction. If this inflammatory environment can be restored, destructive arthritis in RA can be prevented.
With the introduction of molecular-targeted agents (MTAs) at the beginning of this century, RA has become a controllable disease. Nevertheless, effective drugs including MTAs require continuous administration. This is because they are still unable to eliminate the cause of the disease. Patients with refractory RA often show a decreased response to treatment over time, suggesting that there underlie the irreversible traits of cytokine dysregulation. For the treatment aiming a closer-to-cure condition, it is necessary to find new approach to restore such traits.
The RA synovium has two abnormalities: morphological and functional ones. The first is the loss of the single-cell-layer structure surrounding the joint cavity followed by abnormal proliferation to form a tumor-like tissue called pannus which is comparable to epithelial-mesenchymal transition (EMT), and the second is the autonomous activation of inflammation-related genes due to epigenetic changes in DNA and the decrease in immune regulatory response due to metabolic changes, etc. Especially, these functional abnormalities seem to be associated with traits of cytokine dysregulation in RA synovium.
Recent chromatin immunoprecipitation sequencing analysis with synovial fibroblasts has shown that EMT-like changes are linked to changes in cytokine production. In RA, compared to osteoarthritis, non-autoimmune joint disease, there were activating histone modifications at the IL-6 locus. Intriguingly, such activation changes were observed also in the loci of EMT marker genes, SNAI1 and COL1A1. These epigenetic changes in the RA synovium seem to be related to irreversible, fixed traits that continue the inflammatory response.
Candidate targets of the trait-restoring therapy for RA include molecules involved in epigenetic plasticity that can restore irreversible changes toward inflammatory nature in the RA synovium.
Maria Greenwald, MD, FACR
Desert Medical Advances
JoAnn Ball, NP
Desert Medical Advances
Denise Garcia, MA
Desert Medical Advances
Abstract
Background: Rheumatoid Arthritis (RA) is associated with an elevated risk of thrombosis, which contributes to increased major adverse cardiovascular events and mortality in individuals with RA aged over 50, as compared to the general population. This increased thrombotic risk is thought to be due to systemic inflammation leading to platelet dysfunction. Additionally, certain RA treatments have been associated with an increased risk of clot formation. We proposed the hypothesis that a shortened bleeding time measurement could serve as an identifying marker for individuals at risk of clotting events. The bleeding time assesses platelet function. Aspirin can reverse the short bleeding time and may prevent the incidence of thrombosis.
Methods: Sequential RA patients over age 50 (n=246) at one center had bleeding time testing at the initial visit and 2 weeks after beginning a medication known to affect coagulation. These were estrogen, rofecoxib, celecoxib, naproxen, ibuprofen, aspirin, tofacitinib, baricitinib, upadacitinib, filgotinib, and anti-coagulants.
Results: The RA control group had a bleeding time of 3.7 + 0.4 minutes. This is a shorter bleeding time than expected in the normal population, where bleeding time is 4 to 7 minutes. The RA patients who developed MACE or thrombotic events had shorter bleeding time at 2.3 + 0.4 minutes, significantly shorter than the RA control group, p<0.001. A shorter bleeding time was demonstrated with COX-2 agents, rofecoxib and celecoxib at less than 2.5 minutes, and JAK agents had short bleeding time from 1.5 to 2.3 minutes, all significantly lower than the control p<0.002. Adding daily 81 mg low dose aspirin to JAK reversed the bleeding time to the control values. A bleeding time measured at less than 3 minutes was associated with higher incident rates of thrombotic events and MACE.
Conclusion: These findings suggest that bleeding time less than 3 minutes may serve as a clinically relevant marker for assessing thrombotic risk in RA patients. Further research with larger cohorts is warranted to validate and expand upon these observations, potentially paving the way for the incorporation of bleeding time testing into the clinical management of RA patients to optimize thrombotic risk assessment and preventive strategies.
George A Karpouzas, MD
Division of Rheumatology, Harbor-UCLA Medical Center and Lundquist Institute for Biomedical Innovation, Torrance, CA, USA
Sarah R Ormseth, PhD
Division of Rheumatology, Harbor-UCLA Medical Center and Lundquist Institute for Biomedical Innovation, Torrance, CA, USA
Elizabeth R Hernandez
Division of Rheumatology, Harbor-UCLA Medical Center and Lundquist Institute for Biomedical Innovation, Torrance, CA, USA
Matthew J Budoff, MD
Division of Cardiology, Harbor-UCLA Medical Center and Lundquist Institute for Biomedical Innovation, Torrance, CA, USA
Abstract
Methods. The sample included 144 patients with complete biomarker data who underwent plaque evaluation with coronary computed tomography angiography; 95 were re-imaged within 6.9±0.3 years. Presence of >5 segments with plaque or coronary artery calcium >100 constituted extensive disease; lesions rendering >50% stenosis were considered obstructive. The Framingham 2008 cardiovascular risk score was included in all models.
Results. Hs-cTnI added to the cardiovascular risk score increased area-under-the curve (AUC) from 0.710 to 0.729 and improved prediction accuracy for baseline plaque presence [Net Reclassification Improvement =0.538 (95% confidence interval 0.143-0.895)] and Integrated Discrimination Improvement (IDI) =0.035 (0.001-0.128). In contrast, a-b2GPI-IgA did not, and the combination offered no added benefit over hs-cTnI alone. While hs-cTnI alone did not predict plaque progression, a-b2GPI-IgA presence did (p=0.005), especially in patients with >median hs-cTnI (p=0.015). In patients with >median hs-cTnI, adding a-b2GPI-IgA to a cardiovascular risk score model predicting progression from non-extensive/non-obstructive to extensive/obstructive plaque increased AUC from 0.796 to 0.878 and improved model precision [IDI=0.277 (0.011-0.946)].
Conclusion. High hs-cTnI significantly improved prediction of baseline plaque presence and may trigger an initial non-invasive coronary atherosclerosis evaluation. A-b2GPI-IgA presence may justify a follow-up interrogation in patients with non-extensive, non-obstructive plaque at baseline.
