Rheumatoid arthritis as a chronic disease.

Health

How to treat chronic disease by breaking the cycle of inflammation in two diseases

By Juman Hijab

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Original date: September 30, 2023  

Updated: October 2, 2023

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Rheumatoid arthritis and Crohn's disease

IBD relief. Symptoms of Crohn's disease. Flickr.com, uploaded Jan 4, 2018.

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handarmdoc. Rheumatoid arthritis as a chronic disease. Flickr.com, taken 4/22/2008.

Many chronic diseases have evidence of elevated molecules in the blood. While the molecule is not the first event that happens, ongoing elevation of that molecule potentiates chronic organ pathology. Let's take two diseases that highlight this phenomenon.


Crohn’s Disease


Crohn's disease is a chronic inflammatory bowel disease that can affect any part of the digestive tract from the mouth to the anus. 

In Crohn’s disease, serum and intestinal levels of IL-6 and sIL-6r are higher than in controls. This correlates with the severity of the intestinal inflammation. Also, the high levels of IL-6 protect immune system cells intensifying the ongoing and chronic intestinal inflammation. 

Unfortunately, pro-inflammatory proteins (like IL-6) induce senescence in susceptible cells. Senescent cells are old and damaged cells that have stopped dividing.

Senescence begets senescence 

Senescent cells are not passive entities. They release harmful substances (SASPs) that damage nearby cells and tissues. Senescence-associated secretory phenotype (SASP) factors are molecules that promote the development of senescence in healthy cells, creating an unhealthy positive feedback loop.

The accumulation of senescent cells in the intestinal lining is thought to be one of the main drivers of Crohn's disease pathogenesis. 


Rheumatoid Arthritis


In rheumatoid arthritis (RA), the synovial membrane, which lines the joints, becomes inflamed and thickened, leading to joint damage and chronic inflammation.

Inflammatory proteins (for example, Interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF alpha) are major contributors to rheumatoid arthritis.

Studies have shown that senescent cell accumulate prematurely in the synovial (joint) tissues in rheumatoid arthritis joints. Not only that, those same cells demonstrate an increased production of pro-inflammatory factors.

In fact, both soluble IL-6 receptor as well as IL-6 levels are increased in the synovial fluid and the serum of RA patients. Moreover, those levels are highly correlated with disease activity. 

The vicious cycle of chronic inflammatory disesae

Thus, there are two abnormal processes that coincide and reinforce  each other to propagate chronic inflammatory states in conditions such as Crohn’s disease and rheumatoid arthritis: 

•Higher levels of pro-inflammatory (senescence-inducing) factors

•Higher infiltration of the tissues with senescent cells


Unfortunately, SASP factors induce senescence changes in cells, which in turn induce the production of additional pro-inflammatory proteins.


Breaking the cycle of chronic inflammation

In any chronic disease; while late intervention can have benefit, early intervention is important to curb the chronic inflammatory process!

In both rheumatoid arthritis and Crohn's disease, disease-modifying drugs target specific inflammatory molecules to interrupt the inflammatory processes driving the disease. For example, TNF and IL-6 inhibitors are used highly effectively in the management of the chronic inflammation that drives joint and intestinal inflammation, in rheumatoid arthritis and Crohn's disease, respectively. Of note, while those therapies have offered significant advances in tailored treatments, they increase the risk of infections. 

Breaking the cycle of chronic inflammation is important as this can lead to improved outcomes and, in some cases, remission.

References: 

  1. Sapart E, Sokolova T, de Montjoye S, Dierckx S, Nzeusseu A, Avramovska A, Meric de Bellefon L, Durez P. Should We Use bDMARDs as an Induction Therapy in Early and Severe Rheumatoid Arthritis? Results at 5 years from the ERA UCLouvain Brussels Cohort. Rheumatol Ther. 2023 Aug;10(4):875-886. doi: 10.1007/s40744-023-00551-3. Epub 2023 May 14. PMID: 37183237; PMCID: PMC10326217.
  2. Neurath MF. Current and emerging therapeutic targets for IBD. Nat Rev Gastroenterol Hepatol. 2017 May;14(5):269-278. doi: 10.1038/nrgastro.2016.208. Epub 2017 Feb 1. Erratum in: Nat Rev Gastroenterol Hepatol. 2017 Oct 11;: PMID: 28144028.
  3. Burmester GR, Panaccione R, Gordon KB, McIlraith MJ, Lacerda AP. Adalimumab: long-term safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn's disease. Ann Rheum Dis. 2013 Apr;72(4):517-24. doi: 10.1136/annrheumdis-2011-201244. Epub 2012 May 5. PMID: 22562972; PMCID: PMC3595151.
  4. Saeed S, Ekhator C, Abdelaziz AM, Naveed H, Karski A, Cook DE, Reddy SM, Affaf M, Khan SJ, Bellegarde SB, Rehman A, Hasan AH, Shehryar A. Revolutionizing Inflammatory Bowel Disease Management: A Comprehensive Narrative Review of Innovative Dietary Strategies and Future Directions. Cureus. 2023 Aug 29;15(8):e44304. doi: 10.7759/cureus.44304. PMID: 37664362; PMCID: PMC10470660.

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