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 Table of Contents  
Year : 2017  |  Volume : 4  |  Issue : 1  |  Page : 52-54

Pancytopenia and stomatitis induced by low-dose methotrexate use

1 Department of Internal Medicine, Malatya State Hospital, Malatya, Turkey
2 Department of Neurology, Malatya State Hospital, Malatya, Turkey

Date of Web Publication19-Dec-2016

Correspondence Address:
Hüseyin Yildiz
Department of Internal Medicine, Malatya State Hospital, Turgut Özal Boulevard Nr: 4, 44330 Malatya
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2348-3334.196068

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Rheumatoid arthritis (RA) is the most common systemic, autoimmune, and chronic inflammatory disease causing symmetrical arthritis in joints. To prevent its progression, disease-modifying drugs are used. Among these, methotrexate (MTX) is the first choice drug. MTX is an agent which blocks deoxyribonucleic acid synthesis by competitively inhibiting folic acid metabolism. During treatment, rare but severe side effects such as pancytopenia, hepatotoxicity, mucositis, and pulmonary toxicity can be seen. In this case, a 76-year-old woman diagnosed with RA developed stomatitis and severe pancytopenia after treatment with low-dose MTX is reported.

Keywords: Methotrexate, pancytopenia, rheumatoid arthritis, stomatitis

How to cite this article:
Yildiz H, Tayci I, Yildiz Ö, Demir MV. Pancytopenia and stomatitis induced by low-dose methotrexate use. CHRISMED J Health Res 2017;4:52-4

How to cite this URL:
Yildiz H, Tayci I, Yildiz Ö, Demir MV. Pancytopenia and stomatitis induced by low-dose methotrexate use. CHRISMED J Health Res [serial online] 2017 [cited 2022 Oct 1];4:52-4. Available from: https://www.cjhr.org/text.asp?2017/4/1/52/196068

  Introduction Top

Methotrexate (MTX) is a folic acid antagonist used in the treatment of neoplastic diseases and chronic inflammatory diseases such as rheumatoid arthritis (RA) because of its anti-inflammatory and immunosuppressive effect. [1] It has several severe side effects such as nausea, stomatitis, bone marrow suppression, hepatic, and pulmonary toxicity. [2] Low-dose MTX-induced pancytopenia is rare but life-threatening complication and occurs in 1.4% of patients. [2] Pancytopenia develops more frequently in the presence of dehydration, high mean corpuscular volume level, hypoalbuminemia, renal failure, advanced age, infection, low folate levels, and lack of concomitant administration of folic acid. [3],[4],[5],[6] In this case, a 76-year-old patient who developed pancytopenia and stomatitis after low-dose MTX treatment without folic acid supplementation is reported.

  Case report Top

Seventy-six-year-old female patient was admitted to the emergency department with complaints of difficulty in opening mouth, oral mucositis, anorexia, malaise, and dyspnea. She had a medical history of rheumatoid arthritis for 3 years, chronic obstructive pulmonary disease, coronary artery disease, and type 2 diabetes mellitus. The patient gave up taking MTX 2 months ago but 2 weeks ago MTX treatment was started again. Weekly 15 mg MTX treatment was given intramuscularly to the patient for 2 weeks, but she had forgotten to take folic acid supplementation together. Three days after taking the second injection, she admitted to the emergency department with the complaints of painful sores in the mouth, difficulty in opening mouth, and dyspnea. Painful ulcers on oral mucosa were detected on physical examination [Figure 1]. Vital signs were stable (fever: 36.2°C, arterial blood pressure: 120/70 mmHg, and pulse rate: 84 bpm and blood oxygen saturation: 87% in room air). Other systemic examination was normal except obese appearance. On admission, the patient was pancytopenic and hypoalbuminemic whereas other laboratory results were normal [Table 1]. After infectious disease consultation, empirically ampicillin 4 × 1 g, ciprofloxacin 2 × 400 mg intravenous daily, nystatin mouthwash 2 × 1, and benzydamine hydrochloride 3 × 1 oral treatment were recommended. In peripheral blood smear examination, hypochromic normocytic anemia, a small number of fragmented cells, 4-5 platelet groups, a few mature lymphocytes, and no atypical cells were detected. No organomegaly or lymphadenopathy was detected in the abdominal ultrasonography. MTX was stopped, and subcutaneous filgrastim 48 million units and oral folic acid 2 × 5 mg treatment were initiated to the patient. Improvement in blood cell count was seen after single-dose filgrastim administration. In the 2 nd day of the treatment, neutropenia disappeared. Hemogram results before discharge of the patient are shown in the table [Table 1].
Figure 1: Stomatitis after methotrexate treatment

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Table 1: Laboratory results at presentation and discharge

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  Discussion Top

RA is a chronic, progressive, autoimmune, inflammatory disease characterized by synovial cell proliferation and destruction in the joints. [7] Disease-modifying drugs having anti-inflammatory effects are used from the early stage of the disease. Among these, MTX which is selective competitive inhibitor of the enzyme dihydrofolate reductase is the first choice of drug. It consequently reduces the production of thymidylate and deoxyribonucleic acid synthesis. Thus, it affects tissues and organ system capable of rapid proliferation such as mucosa, gastrointestinal system, and bone marrow. Pancytopenia is a rare but severe side effect of MTX. Ohosone et al. reported 4 (1.4%) pancytopenia cases at the end of a 33.2-month long-term follow-up of 284 patients during MTX treatment. [2] In another study, Nakazaki et al. reported only one (0.002%) pancytopenia case at the end of a 60-month long-term follow-up of 420 patients treated with MTX. [8] Gutierrez-Ureρa et al. found pancytopenia ratio 1%-2% in RA patients taking MTX treatment. [9]

The mechanism of development of MTX-induced pancytopenia is not clear. It is commonly seen in some patients having several risk factors such as dehydration, high MCV level, hypoalbuminemia, daily MTX intake instead of weekly, renal failure, low folic acid level, lack of concomitant folic acid supplementation, advanced age, infection, and polypharmacy. [3],[4],[5],[6] In our case, advanced age of the patient, polypharmacy, hypoalbuminemia, and lack of concomitant administration of folic acid could facilitate the development of pancytopenia.

In case of MTX-induced pancytopenia, granulocyte-monocyte colony-stimulating factor (G-CSF) should be initiated after bone marrow biopsy and excluding the pancytopenia secondary to malignancy. [10],[11] In our case, we did not need to do bone marrow biopsy because of sudden onset of pancytopenia after MTX use and normal blood count before the treatment. Improvement in hemogram was seen after single-dose G-CSF administration.

MTX-related stomatitis is observed 2%-10%. [12] In a study, Morgan et al. showed that concomitant administration of folic acid to MTX treatment reduces the rate of adverse effects such as stomatitis and hepatotoxicity. [13] Folic acid, benzydamine hydrochloride, and nystatin oral suspension were initiated to our patient, and significant improvement observed in mucocutaneous lesions.

Finally, MTX is an effective agent used in the treatment of RA. To avoid from possible side effects such as stomatitis, pancytopenia, and hepatotoxicity during MTX treatment, it will be appropriate informing patient about the side effects of drugs, concomitant administration of folic acid, identifying risk factors of patients, blood count, and biochemistry follow-up. Thus, possible side effects and unnecessary medical expenses will be prevented.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Harris ED, Budd RC, Genovese MC, Firestein GS, Sargent JS, Sledge CB. Kelley′s Textbook of Rheumatology. 7 th ed. Chap 66. Philadelphia, Pa: Saunders Elsevier; 2005.   Back to cited text no. 1
Ohosone Y, Okano Y, Kameda H, Hama N, Matsumura M, Nojima T, et al. Toxicity of low-dose methotrexate in rheumatoid arthritis - clinical characteristics in patients with MTX-induced pancytopenia and interstitial pneumonitis. Ryumachi 1997;37:16-23.  Back to cited text no. 2
Lim AY, Gaffney K, Scott DG. Methotrexate-induced pancytopenia: serious and under-reported? Our experience of 25 cases in 5 years. Rheumatology (Oxford) 2005;44:1051-5.  Back to cited text no. 3
Guler N, Kisacik B, Utku U, Cevik A, Ercolak V, Ecemis G, et al. Low dose methotrexate associated pancytopenia in a patient with rheumatoid arthritis. Turk J Phys Med Rehabil 2008;54:79-81.  Back to cited text no. 4
Yang CP, Kuo MC, Guh JY, Chen HC. Pancytopenia after low dose methotrexate therapy in a hemodialysis patient: case report and review of literature. Ren Fail 2006;28:95-7.  Back to cited text no. 5
Preet Singh Y, Aggarwal A, Misra R, Agarwal V. Low-dose methotrexate-induced pancytopenia. Clin Rheumatol 2007;26:84-7.  Back to cited text no. 6
Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet 2001;358:903-11.  Back to cited text no. 7
Nakazaki S, Murayama T, Katoh S. Cytopenia associated with low dose pulse methotrexate in the treatment of rheumatoid arthritis. Ryumachi 2001;41:929-37.  Back to cited text no. 8
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. 9
Steger GG, Mader RM, Gnant MF, Marosi C, Lenz K, Jakesz R. GM-CSF in the treatment of a patient with severe methotrexate intoxication. J Intern Med 1993;233:499-502.  Back to cited text no. 10
Yoon KH, Ng SC. Early onset methotrexate-induced pancytopenia and response to G-CSF: a report of two cases. J Clin Rheumatol 2001;7:17-20.  Back to cited text no. 11
Bauer J, Fartasch M, Schuler G, Schell H. Ulcerative stomatitis as clinical clue to inadvertent methotrexate overdose. Hautarzt 1999;50:670-3.  Back to cited text no. 12
Morgan SL, Baggott JE, Vaughn WH, Austin JS, Veitch TA, Lee JY, et al. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial. Ann Intern Med 1994;121:833-41.  Back to cited text no. 13


  [Figure 1]

  [Table 1]

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2 Side effects of methotrexate therapy for rheumatoid arthritis: A systematic review
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