Rheumatoid Arthritis And Inflammatory Bowel Disease

Chronic autoimmune diseases rheumatoid arthritis and inflammatory bowel disease can have a major negative influence on a person's health and quality of life. Even though they affect separate body areas, dysregulated immune responses and chronic inflammation are fundamental underlying processes shared by both rheumatoid arthritis and inflammatory bowel disease. Despite being very uncommon, coexisting rheumatoid arthritis and inflammatory bowel disease can be difficult to diagnose and treat because of overlapping symptoms, interactions with medications, and a higher risk of complications. It takes a diverse team of healthcare professionals to provide comprehensive care that is necessary for treating rheumatoid arthritis and inflammatory bowel disease, maximising treatment outcomes, and enhancing patients' general well-being.

Introduction

Rheumatoid Arthritis (RA) is an autoimmune disease commonly developed among middle-aged to older-aged individuals. Its clinical presentation includes inflammation and swelling in the synovial joints and extra-articular places. This condition usually worsens over time from prolonged joint inflammation, which causes joint destruction from bone erosion and loss of cartilage.¹ Inflammatory Bowel Disease (IBD) in a general term is characterised by chronic severe inflammation in the gastrointestinal tract (GI), which is caused by a prolonged inappropriate immune response to gut microflora. IBD can be categorised into two types. Ulcerative colitis (UC) and Crohn’s Disease (CD), are similar but each has distinctive characteristics. UC involves inflammation in the colonic mucosa, whereas CD involves transmural (across the entire wall of epithelial cells) ulceration of the GI tract, but it is often centralised in the terminal ileum and colon.² 

Rheumatoid arthritis

Genetics play a significant role in the development of RA. As mentioned previously about the HLA genes, RA development is specifically associated with the HLA-DRB1 gene variant.⁷ While not fully understood yet, RA development has also shown a weak association with polymorphism in other genes. On top of genetic factors, RA gene variant gene expression in the genetically predisposed host is usually triggered by other environmental factors. For example, smoking cigarettes, which have numerous carcinogenic components, has shown a positive correlation with an increased risk of developing RA.⁸ Another environmental factor includes diet and obesity. An unhealthy diet with high calories and low fibre increases the risk of obesity and simultaneously also increases the risk of developing RA.⁹  

The most common symptoms associated with RA are joint pain and swelling, which usually manifest gradually over weeks or months. It starts predominantly in the small joints of hands and feet, then slowly follows to larger joints. The hallmark of RA is osteoarthritis, the stiffness, particularly morning stiffness of the joints. In severe cases of manifestation, the movement of joints would be painful to the point of debilitation. 

Diagnosis for rheumatoid arthritis

Diagnosis for early stages of RA is challenging because there are no pathognomonic lab tests for RA, hence turning to the use of imaging studies. Magnetic resonance imaging (MRI) and ultrasonography are useful in capturing radiographic evidence of bone erosion, which occurs in RA. MRI scans can also reveal synovial thickening – a telltale sign of future prognosis on bony erosions. The traditional method of diagnosing RA involved the presence of at least four characteristics of the following criteria for at least six weeks:¹ 

• Morning stiffness;
• Arthritis of three or more joints;
• Arthritis of the hands;
• Symmetric arthritis;
• Elevated acute phase reactants;
• Elevated rheumatoid factor;
• Radiologic evidence of RA. 

However, it was deemed too vague, and it is also unable to detect early stages of RA, preventing early intervention. Hence, the 2010 American College of Rheumatology and the European League Against Rheumatism (ACR/EULAR) developed a new diagnostic procedure, which can be seen in the following link. 

Treatment for rheumatoid arthritis

There is no cure for RA, but its symptoms and disease manifestation can be mitigated. Disease-modifying antirheumatic drugs (DMARDs) could be administered to help with reducing inflammation. Its mechanism of action involves interference in pathways within the inflammatory cascade. There are two types of DMARD: conventional, which suppresses the whole immune system, and biological, which suppresses specific parts of the immune system. Methotrexate is the most commonly used conventional DMARD for the initial treatment of RA.¹⁰ As for biological DMARDs, they can either interfere with cytokine production or function, inhibit the second messenger in the T-cell activation pathway, or deplete B-cells.¹⁰ Usually a combination of both conventional and biological DMARDs is implemented as treatment regimens. Non-steroidal anti-inflammatory drugs (NSAIDs) are also normally administered to help alongside DMARDs with reducing inflammation and relieving pain.¹¹ 

Inflammatory bowel disease

In a general sense, IBD consists of severe abdominal pain and diarrhoea. This can be caused by defective tight junctions (proteins found in the intestinal epithelium), which cause severe inflammation due to the lack of barrier function. With the excessive inflammatory reactions, there would be an increase in antimicrobial activity that speeds up the deterioration of the epithelium, worsening the inflammation. Specifically, IBD consists of two different types of conditions, ulcerative colitis (UC) and Crohn’s disease (CD).¹² These two types of intestinal disease are categorised by their differing location and depth in the bowel wall. Neither disorder is curable, and both are associated with a genetic predisposition. In addition, they both increase the risk of colorectal cancer.² 

UC affects the rectum (proctitis) and also possibly extends into and beyond the sigmoid (proctosigmoiditis and distal ulcerative colitis), taking up the entire colon (pancolitis). It progresses from the rectum to the proximal colon in an uninterrupted fashion. The mucosal inflammation leads to oedema, ulcers, bleeding, and electrolyte losses, causing pain, diarrhoea, and blood in stool.² As for the CD, it involves all layers of the bowel (transmural) with ulcerations in any portion of the GI tract, although often found in the terminal ileum and colon. It causes malabsorption of water, bile salts, and fatty acids (the main function of the colon), hence causing a heightened risk of developing kidney disease and gallstones.² 

IBD can present as tenesmus (sensation of incomplete evacuation), abdominal pain, chronic diarrhoea, blood or mucus in stool, and rectal bleeding.¹² For more severe cases with a toxic megacolon, severe pain, fever, and abdominal distension could be presented. In these cases, emergency surgery could be considered due to its high morbidity if missed.² There can also be a slight difference in clinical presentation between UC and CD. UC may exhibit constipation if the illness is limited to the rectum and pain in the left lower quadrant. As for CD, it can present as right lower quadrant abdominal pain, with more common nausea, anal fistulas, and abscesses. 

Diagnosis of inflammatory bowel disease

The diagnosis of IBS consists of a combination of clinical observations, endoscopic biopsies, imaging studies, and inflammatory laboratory markers. In blood tests, the presence and level of microcytic anaemia, leukocytosis, and thrombocytosis are tested. CD patients may have higher levels of perinuclear antineutrophil cytoplasmic and anti-Saccharomyces cerevisiae antibodies.² For stool tests, faecal calprotectin levels are used as an inflammatory lab marker for intestinal inflammation as well as to eliminate possible past hypotheses of parasitic organisms' presence. 

Barium studies are also conducted to characterise either UC or CD. In UC, barium imaging shows a lead pipe appearance. As for the CD, proctitis and/or thumb printing are indicative of mucosal inflammation. Additionally, it displays the development of strictures and skip lesions in the ileum. Like RA, imaging studies also help with diagnosis. Ultrasounds are used to rule out ileal disease, MRI for identifying rectal fistulas, and computed tomography (CT) is commonly used to evaluate for bowel obstruction and perforation. 

Treatment options for inflammatory bowel disease

Like RA, there is no cure for IBD, but treatment regimens aim to reduce and maintain remission. Aminosalicylates (also known as 5-ASAs) help inflammation by allowing tissues the chance to heal without extra inflammatory burden. Corticosteroids, such as prednisolone, are an alternative type of medicine used to reduce inflammation. Like RA, colectomy and ileostomy are also options when the condition worsens substantially. Immunosuppressants include common use of azathioprine, mercaptopurine, and methotrexate.¹³ Biological medicines, stronger ones, are manufactured in living organisms (e.g., recombinant DNA technology) to produce a stronger and bigger molecule as medicine, which also allows better specificity and selectivity. 

Relationship between rheumatoid arthritis and inflammatory bowel disease

Several research studies conducted have shown that genetics play a significant role in the development of RA and IBD. Particularly, the Human Leukocyte Antigen (HLA) gene is said to be correlated with RA and IBD. The HLA-B27 (interleukin 15, IgA) gene variant causes certain groups of people to be susceptible to luminal microbiota (microbial in the lumen) that triggers arthritis.¹⁴ The GI tract also has a unique luminal microbiome, and hence the hypothesis of the correlation of RA and IBD was brought forth.³ In this particular Mendelian randomisation study by Meisinger and Freuer on the association between RA and IBD, they found a positive correlation between genetically predicted RA on the development of IBD. UC and CD development specifically suggest that RA plays a causal role in pathogenesis, which causes IBD.⁴ In RA, proinflammatory cytokines are of great importance in the inflammatory immune response in RA as well as IBD.⁵ It is possible that their similar nature is due to the fact that they share a common inflammatory pathway.⁶ 

According to this review article that focuses on investigating the co-occurrence of RA and UC, there have been several different studies that have shown a positive correlation between RA and UC, but there have also been studies showing the opposite.¹⁴ In a study conducted, the authors found that in patients with HLA-B27 and CD, there were abnormalities in the sacroiliac joints seen through MRI scans. However, this hypothesis was dismissed due to insufficient direct mechanistic evidence.³ On the other hand, other studies have found that people with RA are at a higher risk of developing IBD, but not the other way around.⁴ 

Summary

Living with either or both diseases is no doubt challenging, seriously impacting the quality of life negatively. It gets in the way of normal life due to chronic pain and fatigue, which can take a toll on mental health as it leads to increased stress, anxiety, and depression. Healthcare professionals in the mental health field and having a good support system can help a lot in managing and coping with pain and stress. Even though the connection between RA and IBD is becoming more well-acknowledged, little research has been done expressly on how to diagnose and treat RA-IBD comorbidity. It is important to acknowledge and understand the relationship between RA and IBD because it could provide insight into tailoring treatment regimens for maximising therapeutic benefits and also minimising adverse side effects by focussing on the specificity and selectivity of drug usage. Awareness of the link between these two diseases can also help with early detection of either condition, allowing for timely intervention that prevents further complications that occur when the condition is left untreated.