Clinico-genetic model to predict methotrexate intolerance in rheumatoid arthritis



Methotrexate is the gold-standard DMARD in rheumatoid arthritis but is often associated with “mild” adverse effects like intolerance or laboratory abnormalities. Although non-life threatening, they are responsible for drug discontinuation in 17–50%. There is limited data on clinical and genetic markers that predict their occurrence.


This prospective study enrolled patients with active rheumatoid arthritis. They were started on methotrexate at a weekly dose of 15 mg, escalated gradually to reach 25 mg which was continued till the end of the study. Intolerance (symptomatic adverse effects) was ascertained by a questionnaire at 4, 8, 16, and 24 weeks. Laboratory testing for occurrence of cytopenia and/or transaminitis was done at the same study visits. Seven SNPs in four genes involved in methotrexate handling were genotyped using real-time polymerase chain reaction.


This study included 110 patients with rheumatoid arthritis who received methotrexate for 24 weeks; the final mean weekly methotrexate dose was 22.0 ± 4.0 mg. Methotrexate intolerance occurred in 40 (37%), common being nausea (and vomiting) in 29 and anxiety (and dizziness) in 9. It was associated with lower BMI at baseline (21.5 ± 3.7, 23.8 ± 4.6 kg/m2, p = 0.01). FPGS rs10106 was significantly associated with intolerance with an allelic odds ratio (95% CI) of 2.02 (1.14–3.57) and the recessive genetic model (AA+AG versus GG) with an odds ratio of 3.8 (95% CI 1.5–9.6, p = 0.004). A model including both BMI and FPGS rs10106 could modestly predict methotrexate intolerance with an accuracy of 66.3%.


A clinical-genetic model including BMI and SNP FPGS 10101 was found to have a modest prediction ability for methotrexate intolerance.

Key Points
Methotrexate intolerance (symptomatic adverse effects) was common and occurred in 37% patients over 6 months.
SNP FPGS rs10106 and low body mass index were associated with methotrexate intolerance.
Clinico-genetic model had a modest ability of 66% for predicting intolerance.

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Methotrexate tablets were received as an educational grant from Zydus Activa (Zydus Cadilla Inc., Ahmedabad, India). We acknowledge the efforts of Mrs. Nidhi Gupta and Mr. Mohinder Kumar for sample collection. We also acknowledge all technical staff of central sophisticated cell of PGIMER for the use of instruments.

Funding information

This work was funded by a grant Asia Pacific League of Associations for Rheumatology (APLAR) (gene polymorphisms) and from the Department of Biotechnology, Government of India (Grant#BT/PR4608/MED/30/800/2012) (methotrexate polyglutamate levels). Mr. Amit Sandhu was supported by ICMR through its Junior Research Fellowship scheme. Mr. Shabeer Ahmad was supported through a Junior Research Fellowship from the Department of Science and Technology (DST), Government of India.

Author information

Planning study: VDhir, AS; collecting data: AS, VDhir; laboratory work: AS, VDhir, VDhaw, JK, AB; analysis and writing: AS, VDhir, VDhaw, JK, AB

Correspondence to Varun Dhir.

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This study was approved by the institutional ethics committee of Post Graduate Institute of Medical Education and Research. All patients gave written informed consent.

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Sandhu, A., Dhir, V., Ahmad, S. et al. Clinico-genetic model to predict methotrexate intolerance in rheumatoid arthritis. Clin Rheumatol 39, 201–206 (2020) doi:10.1007/s10067-019-04770-4

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  • ABCB1
  • Folate
  • Folate antagonist
  • FPGS
  • GGH
  • Methotrexate
  • Methotrexate polyglutamate
  • Mutation
  • RFC
  • Rheumatoid arthritis
  • Single nucleotide polymorphism