The impact of folate pathway variants on the outcome of methotrexate therapy in rheumatoid arthritis patients

Azhar M Nomair; Abeer Abdelati; Fatma I Dwedar; Rehab Elnemr; Yasmine N Kamel; Hanan M Nomeir

doi:10.1007/s10067-024-06892-w

The impact of folate pathway variants on the outcome of methotrexate therapy in rheumatoid arthritis patients

Clin Rheumatol. 2024 Mar;43(3):971-983. doi: 10.1007/s10067-024-06892-w. Epub 2024 Feb 5.

Authors

Azhar M Nomair¹, Abeer Abdelati², Fatma I Dwedar³, Rehab Elnemr⁴, Yasmine N Kamel³, Hanan M Nomeir³

Affiliations

¹ Department of Chemical Pathology, Medical Research Institute, Alexandria University, Alexandria, Egypt.
² Department of Internal Medicine, Rheumatology and Clinical Immunology Unit, Faculty of Medicine, Alexandria University, Alexandria, Egypt. abir.ibrahim@alexmed.edu.eg.
³ Department of Medical Biochemistry, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
⁴ Department of Physical Medicine Rheumatology and Rehabilitation, Faculty of Medicine, Alexandria University, Alexandria, Egypt.

Abstract

Background: There are currently no validated criteria that entirely explain or predict response to methotrexate (MTX) treatment in rheumatoid arthritis (RA). We tried to identify the connection between three variants (RFC1 G80A (rs1051266), TYMS 2R/3R (rs34743033), and ATIC C347G (rs2372536)) in the folate pathway of MTX metabolism and the response to MTX monotherapy in a cohort of RA cases.

Methods: A prospective study on 100 RA patients on MTX monotherapy was performed. Disease activity was measured at the start of treatment and 6 months after treatment with MTX. The patients were then split into two groups: those who responded to the treatment and those who did not. The molecular genetic study for the RFC1 (G80A) variant was employed via the PCR-restriction fragment length polymorphism (PCR-RFLP) technique, the ATIC (C347G) variant was performed using TaqMan allelic discrimination real-time PCR, and the tandem repeat sequences of TYMS (2R/3R) were amplified by conventional PCR and detected by agarose gel electrophoresis.

Results: The genotype distribution of RFC-1 (G80A) showed significant variations among non-responders and responders in the recessive genetic model. A significant difference was found in TYMS (2R/3R) in the dominant and heterozygous genetic models. However, ATIC (C347G) genotype frequency did not exhibit substantial link with drug response in all genetic models. Furthermore, the genotype and allele rates of the analyzed variants did not show any significant association with adverse events in all genetic models.

Conclusion: The 80AA genotype of RFC-1 G80A and the 2R/3R or 3R/3R genotypes of TYMS 2R/3R are more vulnerable to the good consequences of MTX therapy. Key Points • Current recommendations support the gold standard role of MTX as a first-line monotherapy for RA patients. However, up to 40% of RA patients do not respond or exhibit partial response to MTX. • Persistent disease activity due to treatment unresponsiveness will affect the long-term outcomes in RA patients. • We aimed, through molecular genetic study, to identify the connection between three variants in the folate pathway of MTX metabolism and the response to methotrexate monotherapy in a cohort of RA patients.

Keywords: ATIC; Methotrexate; RFC-1; Rheumatoid arthritis; TYMS; Variant.

MeSH terms

Antirheumatic Agents* / adverse effects
Arthritis, Rheumatoid* / chemically induced
Arthritis, Rheumatoid* / drug therapy
Arthritis, Rheumatoid* / genetics
Folic Acid / therapeutic use
Humans
Methotrexate
Polymorphism, Single Nucleotide
Prospective Studies

Substances

Methotrexate
Antirheumatic Agents
Folic Acid