The Role of Clock Genes in Maintaining Circadian Rhythm and Rheumatoid Arthritis Pathophysiology.

Rheumatoid arthritis (RA) is a chronic, progressive autoimmune condition that affects up to 1% of the world population and symmetrically affects the joints leading to joint stiffness and decreased mobility. RA patients present with increased pain and chronic inflammation within their joint spaces, which researchers have linked to poorer sleep patterns, including difficulty falling asleep and non-restorative sleep. As such, identifying mediators of poor sleep quality among RA patients may improve their long-term quality of life. More recently, researchers identified an association between chronic inflammation in RA patients and their circadian rhythm. Altered circadian rhythms negatively impact the hypothalamic-pituitary-adrenal (HPA) axis and lead to altered cortisol release. Cortisol has shown to have a strong anti-inflammatory effect; when dysregulated, it may lead to increased pain experienced in RA patients. This literature review aims to provide insight into how chronic inflammation tied to RA pathophysiology may affect clock genes that are involved in maintaining the circadian rhythm. Specifically, this review focused on four common clock genes found dysregulated in RA patients: circadian locomotor output cycles kaput (CLOCK), brain and muscle ARNT like-1 (BMAL1), period (PER), and cryptochrome (CRY). Of the four clock genes discussed in this review, BMAL1 and PER are the most well-studied of the affected genes. Further knowledge surrounding clock genes and their dysregulated expression in RA may help guide therapy decisions for RA patients. Traditionally, disease-modifying antirheumatic drugs (DMARDs) have been used as first-line therapy for RA patients. Meanwhile, chronotherapy, optimizing drug release in a timed manner, has shown positive results in RA patients as well. Because of the association of altered circadian rhythms with increased symptom severity in RA patients, it seems highly plausible that DMARD therapy with chronotherapy may be an ideal therapeutic regimen for RA.

Oral Microbiome in Pre-Rheumatoid Arthritis: The Role of Aggregatibacter Actinomycetemcomitans in Bacterial Composition.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that symmetrically affects the joints, eventually leading to cartilage and tissue destruction. While there are multiple etiologies for RA, from environmental to genetic risk factors, periodontal disease (PD) may contribute to the acceleration of RA symptoms in pre-rheumatoid arthritis (pre-RA) and RA patients. While PD is caused by multiple oral bacteria, this review explains the role of Aggregatibacter actinomycetemcomitans (Aa) in the pathogenesis of pre-RA and RA based on 13 primary articles. This paper focuses on the Aa virulence factor leukotoxin A (LtxA) because it has been reported to cause cellular destruction and inflammation in the oral cavity that can accelerate the development of RA. Individuals who are classified as pre-RA may benefit from periodontal screening to further reduce their risk of developing advanced RA. Additionally, they may benefit from earlier pharmacological therapy for RA using disease-modifying anti-rheumatic drugs (DMARD) and antibacterial treatment.

Current pharmacological approaches and potential future therapies for Celiac disease.

Celiac Disease (CeD) is estimated to currently affect 2 million Americans in the United States. This autoimmune disorder occurs when the consumption of gluten-based products leads to an inflammatory response in the small intestine. Over time, this inflammatory response permanently damages the villi in the small intestine. Celiac disease patients generally present with fatigue, diarrhea, and weight loss due to the disease. The current gold standard for diagnosing CeD is the endoscopy with duodenal biopsy indicating villous atrophy and crypt hyperplasia. No FDA-approved medication exists for the treatment of CeD and the only recommended course to alleviate CeD induced symptoms is to abstain from consuming any gluten-based products. There are several clinical trials actively developing and testing pharmacological approaches to treat CeD. Two of the further advanced clinical trials include AT-1001 (Larazotide acetate) and IMGX-003 (Latiglutenase; formerly known as ALV003) therapies. These drugs aim to alleviate celiac disease-induced symptoms using two different approaches. AT-1001 aims to close the villi's tight junctions, while IMGX-003 acts as a gluten endopeptidase that degrades gluten before being absorbed in the small intestine. This review article summarizes the various preclinical research and clinical trials being conducted and specifies the mechanism by which these drugs function.