AUTHOR=Zhang Yuzhuo , Lin Jiangpeng , You Zhixuan , Tu Hengjia , He Peng , Li Jiarong , Gao Rui , Liu Ziyu , Xi Zhiyuan , Li Zekun , Lu Yi , Hu Qiyuan , Li Chenhui , Ge Fan , Huo Zhenyu , Qiao Guibin 

TITLE=Cancer risks in rheumatoid arthritis patients who received immunosuppressive therapies: Will immunosuppressants work?

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1050876

DOI=10.3389/fimmu.2022.1050876

ISSN=1664-3224

ABSTRACT=BACKGROUND
Exploring the cancer risks of rheumatoid arthritis (RA) patients with disease-modifying anti-rheumatic drugs (DMARDs) can help to detect, evaluate, and treat malignancies at an early stage for these patients. Thus, a comprehensive analysis was conducted to determine cancer risks of RA patients using different types of DMARDs and analyzed their relation with tumor mutational burdens (TMBs) reflecting immunogenicity.

METHODS
A thorough search of PubMed, EMBASE, Web of Science and Medline was conducted up to August 20, 2022. Standardized incidence ratios (SIRs) were constructed with a random-effect model to determine risks for different types of malignancies by comparison with general population. We also analyzed the correlation between SIRs and TMBs using linear regression (LR).

RESULTS
22 studies in total, data were available on 371,311 RA patients receiving different types of DMARDs, 36 kinds of malignancies, and 4 regions. Overall cancer risks were 1.15 (SIR 1.15; 1.09-1.22; P<0.001) and 0.91 (SIR 0.91; 0.72-1.14; P=0.402) in RA populations using conventional synthetic DMARDs (csDMARDs) and biologic DMARDs (bDMARDs), respectively. RA patients taking DMARDs displayed a 1.77-fold lung cancer risk (SIR 1.77; 1.50-2.09; P<0.001), a 2.04-fold multiple myeloma risk (SIR 2.04; 1.71-2.44; P<0.001) and a 2.15-fold lymphoma risk (SIR 2.15; 1.78-2.59; P<0.001). Correlation coefficients between TMBs and SIRs were 0.22 and 0.29 taking csDMARDs and bDMARDs , respectively.

CONCLUSION
We demonstrated a cancer risk spectrum of RA populations using DMARDs. Additionally, TMB was not associated with elevated cancer risks in RA patients following immunosuppressive therapy, which confirmed that iatrogenic immunosuppression might not increase cancer risks in patients with RA.

INTERPTETATION
Changes were similar in cancer risk after different immunosuppressive treatments, and correlations were lacked between SIRs and TMBs. These suggest that we should look for causes of increased risks from RA disease itself, rather than using different types of DMARDs. 

SYSTEMATIC REVIEW REGISTRATION 
PROSPERO protocol ID CRD42021232432

KEYWORDS
Rheumatoid Arthritis. Tumor mutational burden. Cancer risk. Immunosuppression Therapy. Immunosuppressant.

HIGHLIGHTS
Our study detailed both overall cancer risk and site-specific cancer risk profiles of RA patients using different types of DMARDs, and explored the relationship between TMBs and cancer risks following immunosuppressive therapies.