Skip to main content

Advertisement

SpringerLink
Log in

Methotrexate-related toxicity in patients with rheumatoid arthritis and renal dysfunction

  • Pharmacovigilance
  • Published:
Rheumatology International Aims and scope Submit manuscript

Abstract

There are limited studies regarding the safety of methotrexate (MTX) in patients with reduced renal function. This study aimed to investigate methotrexate (MTX)-related toxicity in patients with rheumatoid arthritis (RA) and renal dysfunction. This retrospective cohort study included patients with RA and renal dysfunction. Renal dysfunction was defined as an estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m2. We classified the patients into two groups according to the onset of renal dysfunction: newly and previously developed group. MTX-associated toxicity included renal toxicity, hepatotoxicity, serious infection, pancytopenia, leukopenia, thrombocytopenia and mucositis. Cox analysis was performed to determine the factors associated with toxicity. The study included 120 patients with RA and renal dysfunction receiving MTX (66: newly developed; 54: previously developed). The median eGFR was 52.1 mL/min/1.73 m2 [IQR 47.1–57.3]. Thirty-five patients (29.2%) experienced toxicity, and the median time to toxicity events was 23 months (IQR 10–57). Toxicity was distributed as follows: leukopenia (10%, 12/120), renal toxicity (5.8%, 7/120), hepatotoxicity (7.5%, 9/120), serious infection (8.3%, 10/120), pancytopenia (5.0%, 6/120), thrombocytopenia (5.8%, 7/120), and mucositis (5.8%, 7/120). The toxicity rate did not differ significantly between newly and previously developed group [23/66 (34.8%) vs. 12/54 (22.2%), P = 0.130]. Multivariate analysis revealed that hydroxychloroquine use (HR 0.425, 95% CI 0.212–0.853, P = 0.016), baseline eGFR (HR 0.938, 95% CI 0.890–0.988, P = 0.015) and being female (HR 10.538, 95% CI 1.375–80.793, P = 0.023) were associated with MTX-related toxicity. Toxicity occurred in approximately 30% of patients with RA and renal dysfunction receiving MTX treatment. Hydroxychloroquine use exhibited a protective effect against MTX-associated toxicity development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  1. Smolen JS, Landewe RBM, Bijlsma JWJ et al (2020) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. https://doi.org/10.1136/annrheumdis-2019-216655

    Article  PubMed  Google Scholar 

  2. Couderc M, Tatar Z, Pereira B et al (2016) Prevalence of renal impairment in patients with rheumatoid arthritis: results from a cross-sectional multicenter study. Arthritis Care Res (Hoboken) 68:638–644. https://doi.org/10.1002/acr.22713

    Article  Google Scholar 

  3. Hickson LJ, Crowson CS, Gabriel SE, McCarthy JT, Matteson EL (2014) Development of reduced kidney function in rheumatoid arthritis. Am J Kidney Dis 63:206–213. https://doi.org/10.1053/j.ajkd.2013.08.010

    Article  CAS  PubMed  Google Scholar 

  4. Saisho K, Yoshikawa N, Sugata K, Hamada H, Tohma S (2016) Prevalence of chronic kidney disease and administration of RA-related drugs in patients with RA: the NinJa 2012 study in Japan. Mod Rheumatol 26:331–335. https://doi.org/10.3109/14397595.2015.1088620

    Article  CAS  PubMed  Google Scholar 

  5. Chiu HY, Huang HL, Li CH et al (2015) Increased risk of chronic kidney disease in rheumatoid arthritis associated with cardiovascular complications—a national population-based cohort study. PLoS ONE 10:e0136508. https://doi.org/10.1371/journal.pone.0136508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mori S, Yoshitama T, Hirakata N, Ueki Y (2017) Prevalence of and factors associated with renal dysfunction in rheumatoid arthritis patients: a cross-sectional study in community hospitals. Clin Rheumatol 36:2673–2682. https://doi.org/10.1007/s10067-017-3804-5

    Article  PubMed  PubMed Central  Google Scholar 

  7. Brown PM, Pratt AG, Isaacs JD (2016) Mechanism of action of methotrexate in rheumatoid arthritis, and the search for biomarkers. Nat Rev Rheumatol 12:731–742. https://doi.org/10.1038/nrrheum.2016.175

    Article  CAS  PubMed  Google Scholar 

  8. Dubey L, Chatterjee S, Ghosh A (2016) Hepatic and hematological adverse effects of long-term low-dose methotrexate therapy in rheumatoid arthritis: an observational study. Indian J Pharmacol 48:591–594. https://doi.org/10.4103/0253-7613.190761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Khanal A, Castelino RL, Peterson GM, Jose MD (2014) Dose adjustment guidelines for medications in patients with renal impairment: how consistent are drug information sources? Intern Med J 44:77–85. https://doi.org/10.1111/imj.12291

    Article  CAS  PubMed  Google Scholar 

  10. Aletaha D, Neogi T, Silman AJ et al (2010) 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 62:2569–2581. https://doi.org/10.1002/art.27584

    Article  PubMed  Google Scholar 

  11. Levey AS, Bosch JP, Lewis JB et al (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 130:461–470. https://doi.org/10.7326/0003-4819-130-6-199903160-00002

    Article  CAS  PubMed  Google Scholar 

  12. Regev A, Bjornsson ES (2014) Drug-induced liver injury: morbidity, mortality, and Hy's law. Gastroenterology 147:20–24. https://doi.org/10.1053/j.gastro.2014.05.027

    Article  PubMed  Google Scholar 

  13. Silva-Fernandez L, De Cock D, Lunt M et al (2018) Serious infection risk after 1 year between patients with rheumatoid arthritis treated with rituximab or with a second TNFi after initial TNFi failure: results from The British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Rheumatology (Oxford) 57:1533–1540. https://doi.org/10.1093/rheumatology/kex304

    Article  CAS  Google Scholar 

  14. Yokus O, Gedik H (2016) Etiological causes of pancytopenia: a report of 137 cases. Avicenna J Med 6:109–112. https://doi.org/10.4103/2231-0770.191447

    Article  PubMed  PubMed Central  Google Scholar 

  15. US Department of Health and Human Services, National Institutes of Health, National Cancer Institute (2017) Common terminology criteria for adverse events (CTCAE) v5.0 https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50. Accessed 20 Feb 2019

  16. Al Ibraheemi AA, Shamoun S (2016) Incidence and risk factors of oral mucositis in patients with breast cancer who receiving chemotherapy in Al-Bashir Hospital. Int J Hematol Oncol Stem Cell Res 10:217–223

    PubMed  PubMed Central  Google Scholar 

  17. Mori S, Hidaka M, Kawakita T et al (2016) Factors associated with myelosuppression related to low-dose methotrexate therapy for inflammatory rheumatic diseases. PLoS ONE 11:e0154744. https://doi.org/10.1371/journal.pone.0154744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rempenault C, Combe B, Barnetche T et al (2020) Clinical and structural efficacy of hydroxychloroquine in rheumatoid arthritis: a systematic review. Arthritis Care Res (Hoboken) 72:36–40. https://doi.org/10.1002/acr.23826

    Article  Google Scholar 

  19. Rempenault C, Combe B, Barnetche T et al (2018) Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis: a systematic review and meta-analysis. Ann Rheum Dis 77:98–103. https://doi.org/10.1136/annrheumdis-2017-211836

    Article  CAS  PubMed  Google Scholar 

  20. Sharma TS, Wasko MC, Tang X et al (2016) Hydroxychloroquine use is associated with decreased incident cardiovascular events in rheumatoid arthritis patients. J Am Heart Assoc. https://doi.org/10.1161/JAHA.115.002867

    Article  PubMed  PubMed Central  Google Scholar 

  21. Wu CL, Chang CC, Kor CT et al (2018) Hydroxychloroquine use and risk of CKD in patients with rheumatoid arthritis. Clin J Am Soc Nephrol 13:702–709. https://doi.org/10.2215/CJN.11781017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Carmichael SJ, Beal J, Day RO, Tett SE (2002) Combination therapy with methotrexate and hydroxychloroquine for rheumatoid arthritis increases exposure to methotrexate. J Rheumatol 29:2077–2083

    CAS  PubMed  Google Scholar 

  23. Lee JY, Luc S, Greenblatt DJ, Kalish R, McAlindon TE (2013) Factors associated with blood hydroxychloroquine level in lupus patients: renal function could be important. Lupus 22:541–542. https://doi.org/10.1177/0961203313476361

    Article  CAS  PubMed  Google Scholar 

  24. Amacher DE (2014) Female gender as a susceptibility factor for drug-induced liver injury. Hum Exp Toxicol 33:928–939. https://doi.org/10.1177/0960327113512860

    Article  CAS  PubMed  Google Scholar 

  25. Wauters M, Elseviers M, Vaes B et al (2016) Polypharmacy in a Belgian cohort of community-dwelling oldest old (80+). Acta Clin Belg 71:158–166. https://doi.org/10.1080/17843286.2016.1148298

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the Scientific Publications Team, Asan Medical Center and Enago (https://www.enago.co.kr) for their language editing.

Funding

The research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Division of Rheumatology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, South Korea

    Jung Sun Lee, Yong-Gil Kim, Chang-Keun Lee, Bin Yoo & Seokchan Hong

  2. Division of Rheumatology, Department of Internal Medicine, Seoul Veterans Hospital, Seoul, South Korea

    Jung Sun Lee

  3. Department of Biomedical Informatics, Asan Medical Center, Seoul, South Korea

    Ji Seon Oh

Authors
  1. Jung Sun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ji Seon Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yong-Gil Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chang-Keun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bin Yoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Seokchan Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JSL, BY, and SH participated in the design of the study. JSL carried out the data collection. JSL, JSO, YGK, CKL, BY, and SH were responsible for the analysis and interpretation of the data. JSL and SH were responsible for drafting the article, and all other authors critically reviewed the article.

Corresponding author

Correspondence to Seokchan Hong.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study complied with the recommendations of the Declaration of Helsinki and was approved by the Institutional Review Board of the Asan Medical Center (2019-03-28/approval number 2019-0407).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, J.S., Oh, J.S., Kim, YG. et al. Methotrexate-related toxicity in patients with rheumatoid arthritis and renal dysfunction. Rheumatol Int 40, 765–770 (2020). https://doi.org/10.1007/s00296-020-04547-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00296-020-04547-y

Keywords

Search

Navigation