RA Linked to Reduced Risk of Colorectal Cancer

Rheumatoid arthritis (RA) is associated with a reduced risk of colorectal cancer, a study revealed.¹

“This effect is caused by immune-mediated inflammation, with IL6R being a key regulatory gene,” wrote investigators, led by Quifan Li, from the Department of Orthopedics at The Affiliated Suqian First People’s Hospital of Nanjing Medical University in China.

Immune-mediated inflammation and cancer have a close relationship. Depending on the state of the body, inflammation can trigger tumor development. The immune system also has anti-tumor properties and immunotherapy targeting the immune system can help many tumor types achieve long-term remission.

A study back in 1978 saw a relationship between RA and the increased risk of lymphoma but this finding could not be generalized to all cancer types.² A report on the risk of solid cancer in RA resulted in inconsistent findings, with some showing RA reduces the tumor risk.³ For instance, a nationwide cohort study found RA patients have a lower risk of gastric, colon, and lung cancer compared to the general population.⁴

Investigators sought to determine whether RA, an inflammatory autoimmune disease that can damage several systems of the body, increased the risk of colorectal cancer.¹ They suspected the abnormal chronic inflammation due to RA, genetic susceptibility, and regulation of immune response in RA treatment may play a part in the presence of malignant tumors.

The team used Mendelian randomization to examine whether a causal relationship exists between RA and pan-cancer, followed by an analysis of the effect of immune-mediated inflammation on cancer. They assessed for autoimmune traits as potential mediators.

From there investigators conducted a large-scale meta-analysis, extracting the standardized incidence rate of malignancy in patients with RA from PubMed, Embase, and Cochrane Library over the past 20 years (January 2003 – November 2023). They searched the terms RA, autoimmune diseases, cancer, tumor, or malignancy. The team only analyzed a tumor if they had > 5 studies, which included:

1. Hematological tumors: Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, and leukemia
2. Solid Cancer: Bladder cancer, brain cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer
3. Specific Types of Cancer: Melanoma

After, investigators performed a pan-cancer analysis on the RA-related genes, leveraging data from the Mendelian randomization analysis, and completed an immune-related analysis on key genes to uncover the association between RA and malignancy. The team collected 150 immune regulatory genes (1 chemokine, 18 chemokine receptors, 21 MHC-related immune genes, 24 immunoinhibitors, 46 immunostimulators) and 60 immune checkpoint pathway genes (24 Inhibitory, 36 Stimulatory).

The study included 2 samples, 1 for RA and 1 for pan-cancer. The RA sample included 19,234 cases and 61,565 controls, and the pan-cancer sample included 70,223 cases and 372,016 controls.

The Mendelian randomization analysis revealed a negative correlation between RA and pan-cancer (odds ratio [OR], 0.996; 95% confidence interval [CI], 0.994 – 0.999; P = .008), with autoimmune traits as the main mediating variable for their causal relationship (OR, 0.87; 95% CI, 0.82 – 0.92; P = 3.21e-06). After removing the mediating exposure factors of autoimmune traits, the autoimmune traits no longer had their causal relationship with pan-cancer (OR, 0.997; 95% CI, 0.926 – 1.07; P = .923. Additionally, RA no longer had a causal relationship with pan-cancer (OR, 0.999; 95% CI, 0.996 – 1.003; P = .642), demonstrating RA reduces the cancer risk through immune inflammation mediation.

A meta-analysis showed RA patients have a significantly greater risk of hematological tumors, bladder cancer, lung cancer, and liver cancer than the general population. Conversely, RA reduced the risk of developing colorectal cancer (95% confidence interval [CI], 0.53 – 0.85).

Moreover, the pan-cancer analysis demonstrated a high expression of RA-related genes was negatively correlated with colon adenocarcinoma, with the IL69 gene having the greatest correlation in colon adenocarcinoma and rectal adenocarcinoma. The negative correlation between IL69 and immune cells was greater in colorectal cancer than in other cancer types.

“We propose a new perspective that although RA has a pathogenic effect on the human body due to immune disorders leading to the secretion of inflammatory factors and activation of immune cells, this immune activation also has an inhibitory effect on certain malignancy,” investigators wrote. “This may be a reasonable explanation for the reduced risk of colorectal cancer in RA patients.”

References

1. ^{Li Q, Zhou L, Xia D, Wang J. Rheumatoid arthritis reduces the risk of colorectal cancer through immune inflammation mediation. J Cell Mol Med. 2024;28(13):e18515. doi:10.1111/jcmm.18515}
2. ^{Klein A, Polliack A, Gafter-Gvili A. Rheumatoid arthritis and lymphoma: incidence, pathogenesis, biology, and outcome. Hematol Oncol. 2018; 36: 733-739. doi:10.1002/hon.2525}
3. ^{Sugimoto N, Tanaka E, Inoue E, et al. Trends in risks of malignancies in Japanese patients with rheumatoid arthritis: analyses from a 14-year observation of the IORRA cohort. Mod Rheumatol. 2023; 33: 715-722. doi:10.1093/mr/roac085}
4. ^{Ko KM, Moon SJ. Prevalence, incidence, and risk factors of malignancy in patients with rheumatoid arthritis: a nationwide cohort study from Korea. Korean J Intern Med. 2023; 38: 113-124. doi:10.3904/kjim.2021.146}