Letter to the Editor
Severe Secondary Bone Marrow Aplasia Due to Methotrexate in a Patient With Late Onset Rheumatoid Arthritis
Aplasia medular grave secundaria a intoxicación por metotrexato en un paciente con artritis reumatoide de inicio senil
Lorena Expósito Pérez
, Juan José Bethencourt Baute, Sagrario Bustabad Reyes
Corresponding author
Servicio de Reumatología, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
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It is recommended as first-line DMARD by the European League against Rheumatism (EULAR) and the American College of Rheumatology (ACR), alone or in combination with other DMARDs and biological agents. The most common side effects associated with the use of low-dose MTX are gastrointestinal manifestations and elevated liver enzymes, followed by neurological symptoms (headache, fatigue, and dizziness) and cytopenias, mainly leucopenia.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In patients with RA treated with MTX, the prevalence of hematologic toxicity, including leukopenia, thrombocytopenia, pancytopenia and megaloblastic anemia, is estimated at 3%.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3</span></a> The degree of pancytopenia, an adverse effect which may be severe and unpredictable, even at low doses of MTX, may be underestimated. The mortality of severe MTX-induced pancytopenia is unknown. In a series of 25 cases reported by the University Hospital of Norfolk and Norwich, it was estimated at 28%.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">We report the case of a male patient aged 82, independent in his daily activities, ex-smoker, recently diagnosed as diabetic and diagnosed with RA 6 years prior. He was treated with MTX at the beginning RA, with oral doses of 7.5<span class="elsevierStyleHsp" style=""></span>mg/week, associated with folinic acid weekly. After 3 years of treatment, with no side effects and the disease being inactive, he suspended MTX and continued monitoring by his primary care physician. The patient came to the emergency room for malaise, bleeding and painful oral ulcers for 2 months and with melenic evacuations in the past week; he did not refer fever at home, and had poor temperature regulation and respiratory symptoms. Upon interrogation he said that since 2 and half months prior he had an exacerbation of joint manifestations; he was again taking MTX orally at doses of 7.5<span class="elsevierStyleHsp" style=""></span>mg but administered daily until the time of hospitalization, without folinic acid and no other medication that could increase the toxicity of MTX. Physical examination included: temperature 38.4<span class="elsevierStyleHsp" style=""></span>°C, blood pressure 85/56<span class="elsevierStyleHsp" style=""></span>mmHg, heart rate 150<span class="elsevierStyleHsp" style=""></span>bpm, respiratory rate 32<span class="elsevierStyleHsp" style=""></span>rpm, baseline oxygen saturation 95%. Mucositis bleeding, petechiae and ecchymosis of the chest and limbs were observed. Cardiac sounds were arrhythmic and he had crackles in the right lung base upon auscultation. In the laboratory analysis we highlighted the following: hemoglobin 7.8<span class="elsevierStyleHsp" style=""></span>g/dl, MCV 103.1<span class="elsevierStyleHsp" style=""></span>fL, WBC 500/mm<span class="elsevierStyleSup">3</span>, neutrophils 160/mm<span class="elsevierStyleSup">3</span>, platelets 3000/mm<span class="elsevierStyleSup">3</span>, prothrombin 56%, creatinine 1.1<span class="elsevierStyleHsp" style=""></span>mg/dl, aspartate aminotransferase 97<span class="elsevierStyleHsp" style=""></span>U/l, alanine aminotransferase 128<span class="elsevierStyleHsp" style=""></span>U/l, total bilirubin 2.80<span class="elsevierStyleHsp" style=""></span>mg/dl (direct 2.10<span class="elsevierStyleHsp" style=""></span>mg/dl), CRP <span class="elsevierStyleMonospace">></span>90<span class="elsevierStyleHsp" style=""></span>mg/l, folate 15.8<span class="elsevierStyleHsp" style=""></span>ng/ml and vitamin B12 514.4<span class="elsevierStyleHsp" style=""></span>pg/ml. Chest X-ray showed interstitial alveolar infiltrates, parahiliar on the right lung. Chest CT revealed diffuse areas of ground-glass opacities, subpleural increased crosslinking in the right upper lobe; laminar atelectasis in the middle lobe; left pleural effusion. Diagnostic thoracentesis included exudate and inflammatory fluid cytology with reactive mesothelial cells. Negative microbiological studies were observed for blood cultures, Legionella and pneumococcal urinary antigen, and cultures of pleural fluid, sputum and urine.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The patient required entry into the ICU for clinical pulmonary sepsis and severe pancytopenia. He had been taking a dose of 7.5<span class="elsevierStyleHsp" style=""></span>mg/day of MTX for more than a month without folinic acid supplementation. The problem was interpreted as toxicity secondary to MTX. He was treated with broad-spectrum antibiotics, hydration, granulocyte colony stimulating factor, folinic acid and IV methylprednisolone. He received several transfusions of packed red blood cells and platelets, and presented episodes of rapid atrial fibrillation which were controlled with amiodarone and beta blockers. The patient had a good clinical and analytical outcome with resolution of pulmonary infiltrates, improvement of mucositis and rapid recovery of the white series and platelets. The red series has had a slower response to treatment, with persistent normocytic anemia 3 months after discharge.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Pancytopenia is a rare complication of treatment with MTX which can sometimes be fatal. In most cases it is transient and recovers after discontinuation of the drug, but in some patients it causes severe and irreversible pancytopenia, which may result in death.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> MTX toxicity can occur in the absence of specific identifiable risk factors, but it has been seen that there are several factors that can affect its development, such as low renal glomerular filtration, advanced age, interaction with other drugs, poor nutritional status with hypoalbuminemia, increased levels of free drug in plasma and hidden chronic liver disease, so this must be taken into account before starting MTX.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,4</span></a> It is estimated that the incidence and prevalence of MTX pneumonitis is 3.9 and 5.5%, respectively, and in most cases drug withdrawal leads to clinical and radiological improvement over a few weeks.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In our case, we assume that pneumonitis was due to MTX because the patient did not refer previous respiratory problems, an X-ray a year earlier showed no interstitial pattern and after discontinuation of the drug there was radiographic improvement within months.</p><p id="par0035" class="elsevierStylePara elsevierViewall">With respect to the prescription dose, there have been numerous warnings to the Spanish Agency for Medicines and Health Products of serious reactions to MTX due to a confusion in the administered dose, taking it daily instead of weekly,<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> which is what happened in our case.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Use extreme caution when prescribing MTX, especially in elderly patients, and careful prescription, not only verbally but also in writing, of the dose to be administered weekly as well as insisting on these to both the patients and the relatives and primary care professionals, are needed in order to avoid serious complications.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Expósito Pérez L, Bethencourt Baute JJ, Bustabad Reyes S. Aplasia medular grave secundaria a intoxicación por metotrexato en un paciente con artritis reumatoide de inicio senil. Reumatol Clin. 2014;10:344–345.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:6 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "C. Salliot" 1 => "D. van der Heijde" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/ard.2008.093690" "Revista" => array:6 [ "tituloSerie" => "Ann Rheum Dis" "fecha" => "2009" "volumen" => "68" "paginaInicial" => "1100" "paginaFinal" => "1104" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19060002" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Low-dose methotrexate-induced pancytopenia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Y. Preet Singh" 1 => "A. Aggarwal" 2 => "R. Misra" 3 => "V. Agarwal" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s10067-006-0301-7" "Revista" => array:6 [ "tituloSerie" => "Clin Rheumatol" "fecha" => "2007" "volumen" => "26" "paginaInicial" => "84" "paginaFinal" => "87" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16636937" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Methotrexate-induced pancytopenia: serious and under-reported? Our experience of 25 cases in 5 years" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "A.Y. Lim" 1 => "K. Gaffney" 2 => "D.G. Scott" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Rheumatology (Oxford)" "fecha" => "2005" "volumen" => "44" "paginaInicial" => "1051" "paginaFinal" => "1055" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pancytopenia secondary to methotrexate therapy in rheumatoid arthritis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S. Gutiérrez-Ureña" 1 => "J.F. Molina" 2 => "C.O. García" 3 => "M.L. Cuéllar" 4 => "L.R. Espinoza" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "1996" "volumen" => "39" "paginaInicial" => "272" "paginaFinal" => "276" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8849378" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Neumonitis secundaria a metotrexate" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "D. Sáenz" 1 => "F.J. Ruiz" 2 => "S. Monón" 3 => "J. Mozota" 4 => "A. Marquina" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "An Med Interna" "fecha" => "2008" "volumen" => "25" "paginaInicial" => "27" "paginaFinal" => "30" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18377192" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0735109704004413" "estado" => "S300" "issn" => "07351097" ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:1 [ "titulo" => "Metotrexato por vía oral: reacciones adversas graves derivadas de la confusión en la dosis administrada" ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:2 [ "fecha" => "2011" "editorial" => "Agencia Española del Medicamento y Productos Sanitarios. MUH (FV)" ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/21735743/0000001000000005/v1_201409070108/S217357431400121X/v1_201409070108/en/main.assets" "Apartado" => array:4 [ "identificador" => "8400" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Letters to the Editor" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/21735743/0000001000000005/v1_201409070108/S217357431400121X/v1_201409070108/en/main.pdf?idApp=UINPBA00004M&text.app=https://reumatologiaclinica.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S217357431400121X?idApp=UINPBA00004M" ]
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| 2022 January | 178 | 68 | 246 |
| 2021 December | 159 | 53 | 212 |
| 2021 November | 127 | 55 | 182 |
| 2021 October | 156 | 69 | 225 |
| 2021 September | 139 | 49 | 188 |
| 2021 August | 169 | 59 | 228 |
| 2021 July | 145 | 35 | 180 |
| 2021 June | 157 | 48 | 205 |
| 2021 May | 175 | 53 | 228 |
| 2021 April | 275 | 110 | 385 |
| 2021 March | 185 | 52 | 237 |
| 2021 February | 106 | 23 | 129 |
| 2021 January | 118 | 26 | 144 |
| 2020 December | 72 | 29 | 101 |
| 2020 November | 92 | 18 | 110 |
| 2020 October | 129 | 30 | 159 |
| 2020 September | 127 | 46 | 173 |
| 2020 August | 151 | 24 | 175 |
| 2020 July | 87 | 17 | 104 |
| 2020 June | 60 | 21 | 81 |
| 2020 May | 41 | 12 | 53 |
| 2020 April | 41 | 11 | 52 |
| 2020 March | 30 | 10 | 40 |
| 2019 January | 2 | 0 | 2 |
| 2018 May | 15 | 0 | 15 |
| 2018 April | 95 | 6 | 101 |
| 2018 March | 148 | 7 | 155 |
| 2018 February | 121 | 6 | 127 |
| 2018 January | 86 | 5 | 91 |
| 2017 December | 104 | 7 | 111 |
| 2017 November | 174 | 6 | 180 |
| 2017 October | 137 | 3 | 140 |
| 2017 September | 111 | 10 | 121 |
| 2017 August | 117 | 8 | 125 |
| 2017 July | 126 | 5 | 131 |
| 2017 June | 147 | 12 | 159 |
| 2017 May | 137 | 9 | 146 |
| 2017 April | 152 | 6 | 158 |
| 2017 March | 208 | 2 | 210 |
| 2017 February | 361 | 6 | 367 |
| 2017 January | 104 | 9 | 113 |
| 2016 December | 186 | 16 | 202 |
| 2016 November | 184 | 6 | 190 |
| 2016 October | 218 | 14 | 232 |
| 2016 September | 258 | 2 | 260 |
| 2016 August | 187 | 10 | 197 |
| 2016 July | 86 | 8 | 94 |
| 2015 December | 2 | 0 | 2 |
| 2015 August | 3 | 0 | 3 |
| 2015 July | 33 | 0 | 33 |
| 2015 June | 60 | 8 | 68 |
| 2015 May | 83 | 16 | 99 |
| 2015 April | 55 | 6 | 61 |
| 2015 March | 60 | 8 | 68 |
| 2015 February | 55 | 3 | 58 |
| 2015 January | 75 | 15 | 90 |
| 2014 December | 67 | 10 | 77 |
| 2014 November | 48 | 11 | 59 |
| 2014 October | 77 | 20 | 97 |
| 2014 September | 34 | 15 | 49 |
Show all
