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Year : 2023  |  Volume : 15  |  Issue : 1  |  Page : 105-107

Methotrexate-induced Neutropenia

Department of Pharmacology, Shrimati Bhikhiben Kanjibhai Shah Medical Institute and Research Center, Vadodara, Gujarat, India

Date of Submission20-Feb-2023
Date of Decision09-Mar-2023
Date of Acceptance10-Mar-2023
Date of Web Publication31-Mar-2023

Correspondence Address:
Kesha Ajaykumar Parmar
31, FF, Shri Krishna Kunj Society, Jetalpur Road, Vadodara - 390 007, Gujarat
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ajprhc.ajprhc_15_23

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Various malignancies, autoimmune disorders such as rheumatoid arthritis (RA), and elective abortions commonly use methotrexate (MTX) for their treatment, which is a folate antagonist. Although many cases of the common side effects of MTX such as nausea, vomiting, and stomatitis have been reported, very few cases of MTX-induced neutropenia have been found in the literature. We have taken a case of neutropenia that developed after the patient took tablet MTX for RA. The case was studied and the causality assessment of the reported adverse drug reaction showed it to be in the category of “probable” according to the WHO-UMC causality categories.

Keywords: Adverse drug reaction, oral lesions, rheumatoid arthritis

How to cite this article:
Parmar KA, Mehta MD. Methotrexate-induced Neutropenia. Asian J Pharm Res Health Care 2023;15:105-7

How to cite this URL:
Parmar KA, Mehta MD. Methotrexate-induced Neutropenia. Asian J Pharm Res Health Care [serial online] 2023 [cited 2023 Jun 8];15:105-7. Available from: http://www.ajprhc.com/text.asp?2023/15/1/105/373371

  Introduction Top

Methotrexate (MTX), which is a folate antagonist, is commonly used in the treatment of various autoimmune disorders, malignancies, and various elective abortions:

  • Many cases of MTX-induced side effects have been observed. Side effects such as gastrointestinal discomforts such as nausea and vomiting, oral lesions, hepatotoxicity, skin rash, hematological toxicity, and pulmonary toxicities are seen commonly. However, only a few cases of severe neutropenia caused by MTX therapy have been reported in the literature[1]
  • MTX has variable consequences. It is an inhibitor of cellular proliferation. Hence, when a patient's oral epithelial cells are affected, mucositis may develop which is supposed to be through the same mechanism. Cytopenia may also develop at times. Increased bruising, bleeding, macrocytic erythrocytes, and an increased risk of infections may be seen due to cytopenia. Unpredictably, by an immunologic or idiosyncratic pattern, neutropenia might develop, and in patients without identifiable risk factors, it is usually independent of dosage.[2]

  Case Report Top

A 60-year-old female patient came to a tertiary care teaching hospital with chief complaints of lesions in the oral cavity. She visited the dermatology outpatient department on June 7, 2022, with the complaint of lesions in the oral cavity along with generalized weakness in the body for 1 week. The patient had a medical history of rheumatoid arthritis (RA) and was on tablet MTX, 10 mg, once a week, from April 7, 2020, to June 7, 2022 (duration 2 years, 2 months). Tablet folic acid 5 mg was also given once weekly along with tablet MTX. She was a known case of type 2 diabetes mellitus for 10 years and was on tablet metformin 500 mg for the same. There was no significant family history. The patient had reduced appetite due to lesions in the oral cavity. Sleep was adequate, and bowel and bladder habits were also regular. On physical examination, multiple aphthous ulcers were seen over the buccal mucosa and mucosal aspect of the lower lip and the patient appeared pale. The Lab investigations [Table 1] were Hb 10.1 g%, Neutrophils 45%, Lymphocytes 50%, Eosinophils 02%, Monocytes 03%, Basophils 00%. The lesions in the oral cavity were fluid filled and multiple. The patient also complained of generalized weakness from June 1, 2022. After the laboratory investigations, MTX was stopped immediately on June 7, 2022, and the patient was started on tablet Cefadrox (cefadroxil) 500 mg, tablet Force (fluconazole) 200 mg, and Dologel (choline salicylate).
Table 1: Laboratory investigation of the patient

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  Discussion Top

Since the 1980s, MTX is often the first-line medication for RA treatment. The multiple mechanisms suggested are folate antagonism, generation of reactive oxygen species, adenosine signaling, alteration of cytokine profiles, and decrease in adhesion molecules among some others. Currently, the most widely accepted explanation for the MTX mechanism in RA is its action on adenosine signaling, given that MTX increases adenosine levels.[3]

The earlier studies stated that immune function in RA patients treated with MTX showed only marginal effects on immune responses. These included proliferative responses to mitogens, measurements of lymphocyte subsets, rheumatoid factor, immunoglobulin production, and immune complexes. The main mechanism of action of MTX might be more anti-inflammatory than immunosuppressive in RA patients. The studies also stated that MTX has crucial effects on the cascade of events initiated by some cytokines (interleukin [IL]-1, IL-6, and tumor necrosis factor), and they play a major role in RA and other inflammatory diseases.[4]

However, new studies showed that the long-held dogma that this disease-modifying antirheumatic drug (DMARD) acts through the folate pathway does not appear to hold up to scrutiny. Recently, a suggestion supported by many independent threads of evidence proposed that MTX has been identified as an inhibitor of JAK/STAT pathway activity. It suggests that many MTX side effects are likely associated with the folate pathway, whereas the DMARD activity of MTX is likely to be largely mediated by its inhibition of JAK/STAT pathway signaling.[5]

  • The usual dose of the drug MTX which is relatively effective and safe in treating RA ranges from 5.0 mg to 25 mg/week.[6] Pneumonitis, liver disease, and cytopenia are the major toxicities caused by MTX.[7] The incidence rate of neutropenia which is caused by MTX ranges from 1.4% to 7%[8]
  • According to the WHO UMC causality categories,[9] a “probable” relationship between neutropenia and MTX therapy was found in our study
  • The usual recommendations during MTX therapy include blood examination before and 2 weeks after initiation of MTX and every 4–8 weeks thereafter.[10] Discontinuation of MTX is advised if the patient develops neutropenia, and intravenous leucovorin rescue within 24 h should be started[2]
  • In summary, we demonstrated the development of neutropenia along with anemia in the patient after MTX treatment for RA.

  Conclusion Top

To identify myelosuppression and to avoid the sequelae of neutropenia, patients on MTX therapy should be regularly monitored with complete blood count, liver function tests, and renal function tests. The primary care physicians should be aware of the complications, as majority of them can be detected in due time and could be prevented by taking precautionary measures.[11]

Ethical consideration

All the information about the case was taken after informing and taking due permission from the patient.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Simms RW, Kwoh CK, Anderson LG, Erlandson DM, Greene JM, Kelleher M, et al. Guidelines for monitoring drug therapy in rheumatoid arthritis. Arthritis & amp; Rheumatism 1996;39:723-31.  Back to cited text no. 1
Gutierrez-Ureña S, Molina JF, García CO, Cuéllar ML, Espinoza LR. Pancytopenia secondary to methotrexate therapy in rheumatoid arthritis. Arthritis Rheum 1996;39:272-6.  Back to cited text no. 2
Friedman B, Cronstein B. Methotrexate mechanism in treatment of rheumatoid arthritis. Joint Bone Spine 2019;86:301-7.  Back to cited text no. 3
Segal R, Yaron M, Tartakovsky B. Methotrexate: Mechanism of action in rheumatoid arthritis. Semin Arthritis Rheum 1990;20:190-200.  Back to cited text no. 4
Alqarni AM, Zeidler MP. How does methotrexate work? Biochem Soc Trans 2020;48:559-67.  Back to cited text no. 5
Borchers AT, Keen CL, Cheema GS, Gershwin ME. The use of methotrexate in rheumatoid arthritis. Semin Arthritis Rheum 2004;34:465-83.  Back to cited text no. 6
Weinblatt ME, Coblyn JS, Fox DA, Fraser PA, Holdsworth DE, Glass DN, et al. Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med 1985;312:818-22.  Back to cited text no. 7
Kinder AJ, Hassell AB, Brand J, Brownfield A, Grove M, Shadforth MF. The treatment of inflammatory arthritis with methotrexate in clinical practice: Treatment duration and incidence of adverse drug reactions. Rheumatology (Oxford) 2005;44:61-6.  Back to cited text no. 8
Zaki SA. Adverse drug reaction and causality assessment scales. Lung India 2011;28:152-3.  Back to cited text no. 9
[PUBMED]  [Full text]  
Kwoh CK, Simms RW, Anderson LG, Erlandson DM, Greene JM, Moncur C, et al. Guidelines for the management of rheumatoid arthritis. Arthritis & amp; Rheumatism 1996;39:713-22.  Back to cited text no. 10
Chabner B, Bertino J, Cleary J, Ortiz T, Lane A, Supko J, et al. Goodman Gilman's the Pharmacological Basis of Therapeutics. 12th ed., Ch. 61. New York: McGraw Hill; 2015. p. 6.  Back to cited text no. 11


  [Table 1]


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