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Challenges and Opportunities in Rheumatoid Arthritis

Challenges and Opportunities in Rheumatoid Arthritis

Leena Äyräväinen, DDS, PhD, Anna Maria Heikkinen, DDS, PhD, and Jukka H Meurman, MD, PhD


This is a narrative review describing how oral infections and diseases are associated with rheumatoid arthritis. From the voluminous oral microbiome, bacteria can get access to circulation through inflamed periodontal tissue, oral mucosa, and carious teeth. This results in the 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 specific autoantibodies such as anti-citrullinated peptide antibodies. 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, such as 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, use saliva substitutes when necessary, and, above all, maintain good oral hygiene. In rheumatoid arthritis, manual dexterity may be impaired, however, making 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, and Geoffrey Littlejohn


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 an 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, and David O. Carpenter, MD


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, Elizabeth Hernandez, MA, Matthew J Budoff, MD, and Sarah R Ormseth, PhD

Division of Cardiology, Harbor-UCLA Medical Center and Lundquist Institute for Biomedical Innovation, Torrance, CA, USA


Objectives. Underweight patients with rheumatoid arthritis incur greater total and cardiovascular mortality compared to overweight or obese patients. 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. The Framingham 2008 modified general cardiovascular risk score was computed at baseline. Obesity was defined as a 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 patients (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.

Ulf Andersson


The recent insight that the immune system is innervated has initiated a search for neural reflex circuits suitable for therapeutic targeting in human inflammatory diseases. The inflammatory reflex, which signals along the vagus system to maintain immune system homeostasis, is the best-characterized such circuit. Proinflammatory molecules, extracellularly released during infectious or sterile injury, are sensed by afferent vagal nerves that transmit this information to the nucleus of the tractus solitarius in the brainstem. The afferent signals generate efferent action potentials that travel from the brainstem via efferent vagal nerves to the spleen and other organs. This culminates in T cell release of acetylcholine, which interacts with α7 nicotinic acetylcholine receptors on immunocompetent cells to inhibit proinflammatory cytokine release. These mobile anti-inflammatory T lymphocytes thus operate both inside and outside compartments innervated by the vagus system.  Therapeutic proof-of-concept anti-inflammatory studies following surgical implantation of electrical vagus nerve stimulators were first conducted in rheumatoid arthritis and Crohn´s disease. Long term use of these devices was uneventful, while the initial surgical procedure caused adverse effects in some patients. The auricular branch of the vagus nerve reaches superficial parts in the concha and tragus in both ears, enabling transcutaneous electrical auricular vagus nerve stimulation (taVNS) as a safer therapeutic alternative. Invasive VNS and taVNS activate similar parts of the central nervous system indicated by functional imaging methods. Pilot taVNS studies in patients with inflammatory diseases have so far been conducted to treat rheumatoid arthritis, osteoarthritis, lupus, pediatric inflammatory bowel diseases, and pediatric nephrotic syndromes.