Chibnall, Rebecca J

Lewis, Hal A

Musiek, Amy C

Nemer, Kathleen M

JAAD Case Reports

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Hal A. Lewis

Kathleen M. Nemer

Rebecca J. Chibnall

Amy C. Musiek

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Methotrexate-induced cutaneous ulceration in 3 nonpsoriatic patients: Report of a rare side effect

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Washington University School of MedicineDigital Commons@BeckerOpen Access Publications2017Methotrexate-induced cutaneous ulceration in 3nonpsoriatic patients: Report of a rare side effectHal A. LewisUniversity of MissouriKathleen M. NemerWashington University School of Medicine in St. LouisRebecca J. ChibnallWashington University School of Medicine in St. LouisAmy C. MusiekWashington University School of Medicine in St. LouisFollow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubsThis Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in OpenAccess Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact engeszer@wustl.edu.Recommended CitationLewis, Hal A.; Nemer, Kathleen M.; Chibnall, Rebecca J.; and Musiek, Amy C., ,"Methotrexate-induced cutaneous ulceration in 3nonpsoriatic patients: Report of a rare side effect." JAAD Case Reports.3,3. 236-239. (2017).https://digitalcommons.wustl.edu/open_access_pubs/5791CASE SERIESMethotrexate-induced cutaneous ulcerationin 3 nonpsoriatic patients: Report of arare side effectHal A. Lewis, BS,a Kathleen M. Nemer, MD,b Rebecca J. Chibnall, MD,b and Amy C. Musiek, MDbColumbia and St. Louis, MissouriKey words: cutaneous; methotrexate; toxicity; ulcers.INTRODUCTIONMethotrexate (MTX) is a commonly prescribedmedication in the treatment of autoimmune condi-tions such as rheumatoid arthritis (RA) and psoriasis.MTX is a folic acid analog and DNA synthesisinhibitor that competitively inhibits dihydrofolatereductase. Well-known side effects of MTX includediarrhea, nausea/vomiting, anorexia, stomatitis, fa-tigue, and malaise.1 Cutaneous ulceration is a lesscommonly described sign of MTX toxicity in patientswith psoriasis. Reported risk factors include rela-tively high MTX dosage, renal impairment, concur-rent nonsteroidal anti-inflammatory drugs, age olderthan 55, folate deficiency, low serum albumin, anddrug interactions.2 MTX-induced cutaneous ulcera-tion in nonpsoriatic patients is rare, with the first casereported in 1998. Since 2011, only 5 cases have beenreported.3 In this case series, we report MTX-inducedcutaneous ulceration in 3 nonpsoriatic patients.CASE 1A 52-year-old woman with RA, hypothyroidism,depression, alcohol abuse, and hepatitis C wasadmitted from an outside hospital for right hip painand right thigh cellulitis, which developed 3 weeksafter a fall and subsequent pubic rami fracture. Onadmission, the patient was found to have pancyto-penia, acute kidney injury, and cholestatic trans-aminitis. MTX level was 0.07 mol/L. She had beentaking 15 mg/wk of MTX for RA for the last 6 months.The dermatology department was consulted forsuperficial ulcerations with crusting and scaling onthe patient’s hands, digits, arms, legs, and upperchest of unclear duration (Fig 1). The primary teamwas concerned for an atypical infectious process, asthe patient’s cellulitis and skin lesions were notimproving on intravenous vancomycin, meropenem,and clindamycin.Punch biopsies for hematoxylin-eosin (H&E)stain and tissue culture on the left forearm andright thigh showed focal dermoepidermal separa-tion (Fig 2) and epidermal dysmaturation (Fig 3).Tissue culture was negative for bacteria, fungus,and atypical mycobacteria. MTX was stopped, thehematology department was consulted, and thepatient was administered 1 dose of leucovorin.Results of a bone marrow biopsy were normal.Given the negative tissue culture results andcontinued cellulitis of the right thigh, the patientwas taken to the operating room for surgicaldebridement, which found pyomyositis, fasciitis,and a hematoma, likely incited from the pelvicfracture. Intraoperative cultures grew methicillin-resistant Staphylococcus aureus. The patient un-derwent several surgical washouts and debride-ments of the right thigh with eventual resolutionon 6 weeks of intravenous vancomycin. Bloodcounts, creatinine, and liver enzymes allAbbreviations used:H&E: hematoxylin-eosin stainMTX: methotrexateRA: rheumatoid arthritisFrom the University of Missouri School of Medicine, Columbiaaand Division of Dermatology, Washington University School ofMedicine.bFunding sources: None.Conflicts of interest: Amy Musiek is a paid consultant for Actelion.All remaining authors have no conflicts of interest to declare.Correspondence to: Rebecca J. Chibnall, MD, Division of Dermat-ology,WashingtonUniversity School ofMedicine, 5201MidamericaPlaza, St. Louis, MO 63129. E-mail: rchibnall@wustl.edu.JAAD Case Reports 2017;3:236-9.2352-5126 2017 by the American Academy of Dermatology, Inc. Publishedby Elsevier, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).http://dx.doi.org/10.1016/j.jdcr.2017.02.002236normalized before discharge, and the patient’s skinlesions slowly resolved off MTX.CASE 2A 56-year-old woman with RA presented to thehospital for new-onset pancytopenia and rash. Shehad been taking 20 mg/wk of MTX for RA for anunclear length of time. On presentation, there werenecrotic, ulcerated nodules with surrounding ery-thema on the left second digit at the proximalinterphalangeal joint, right knee, and left dorsalfoot (Fig 4). The patient first noticed these painful,enlarging lesions 3 months prior after injuring herfingers on rose thorns in her garden. Before admis-sion, the patient had received courses of amoxicillin,cephalexin, and sulfamethoxazole/trimethoprimwithout improvement.Laboratory results showed pancytopenia, and aninfectious workup was negative. MTX level was0.05 mol/L. Two punch biopsies for H&E of theleft knee showed prominent epidermal dysmatura-tion with nuclear pleomorphic and atypical mitoticfigures (Fig 5). The patient’s MTX was stopped, andleucovorin was administered, which resulted inresolution of the cutaneous ulcerations.CASE 3A 52-year-old woman with RA, type II diabetes,hypertension, and hyperlipidemia was admitted tothe medical intensive care unit from an outsidehospital for mouth ulcers, skin rash, fevers, acutekidney injury, and pancytopenia with an absoluteneutrophil count of 0. On physical examination, thepatient displayed periorbital scaling and thick hem-orrhagic crusting of her hard and soft palates. Thepatient had thin, crusted ulcerations on the medialthighs and an eroded plaque underneath the pannus(Fig 6). At the outside hospital, the patient hadreceived acyclovir, piperacillin/tazobactam, flucon-azole, daptomycin, and anidulafungin.The patient was unable to provide a historyregarding symptoms or medications, but chart re-view found she had been taking adalimumab,leflunomide, and MTX, 25 mg/wk, for at least2 months before presentation. A viral swab forherpes simplex virus polymerase chain reactionwas negative. The patient’s mucositis was attributedto MTX toxicity versus erosive lichen planus as aparadoxical effect of her recently initiated tumornecrosis factor inhibitor. MTX level was less than0.04 mol/L. Punch biopsy findings for H&E of theFig 1. Superficial ulcerations with crusting and scaling on the hand, digits, arm, and shin.Fig 2. Histologic examination of a punch biopsy taken from the left forearm shows a focalsubepidermal split with epidermal necrosis. (H&E; original magnifications: left,310 and right,320.)JAAD CASE REPORTSVOLUME 3, NUMBER 3Lewis et al 237right thigh displayed epidermal dysmaturation anddyskeratosis. Because of concern for MTX toxicity,leucovorin was administered, and MTX, lefluno-mide, and adalimumab were stopped. The patient’smucositis and cutaneous lesions improvedthroughout her hospital stay.DISCUSSIONMTX-induced cutaneous ulceration in psoriaticpatients is a rare side effect of low-dose MTXtreatment and can be an indicator of life-threatening pancytopenia.4 Ulceration caused byMTX toxicity in nonpsoriatic patients is even morerare. In this case series, we report MTX-inducedcutaneous ulceration in 3 nonpsoriatic female pa-tients with rheumatoid arthritis. Similar to previouslyreported cases, cutaneous ulceration resolved in ourpatients after discontinuation of MTX.1,2,5The histologic features of MTX-induced cuta-neous toxicity are focal dermoepidermal separationwith keratinocyte necrosis and dystrophy, specif-ically cytologic atypia and dysmaturation.2,6 Biopsiesof lesions from all 3 patients displayed keratinocytedystrophy. Case 1 also displayed focal dermoepi-dermal separation. These pathology findingsconfirm that the cutaneous ulcerations wereFig 3. Histologic examination of a punch biopsy taken from the right thigh shows epidermaldysmaturation and a mixed dermal inflammatory infiltrate with eosinophils. (H&E; originalmagnifications: left, 310 and right, 320.)Fig 4. Necrotic, ulcerated nodules with surrounding erythema on the left second digit at theproximal interphalangeal joint, right knee, and left dorsal foot.Fig 5. Histologic examination of a punch biopsy taken from the left knee shows epidermaldysmaturation with nuclear pleomorphism and atypical mitotic figures. (H&E; originalmagnifications: left, 310 and right, 320.)JAAD CASE REPORTSMAY 2017238 Lewis et alsecondary to MTX toxicity and not infection, whichwas a suspected cause of ulceration in all 3 cases.Case 1 was complicated by right thigh pyomyositis;however, this finding could not explain the cuta-neous ulcerations elsewhere on her body.There is paucity of data on the correlationbetween cutaneous toxicity caused by low-doseMTX treatment (defined as\50 mg/m2) and serumMTX levels. Serum drug levels are monitoredduring high-dose therapy (defined as [500 mg/m2) for treatment of malignancies and are used toidentify the need for leucovorin rescue. SerumMTX concentrations suggesting increased risk fortoxicity after high-dose therapy are 10 mol/L after24 hours, 1 mol/L after 48 hours, and 0.1 mol/Lafter 72 hours after MTX administration.7 Each ofour 3 patients received leucovorin rescue andstopped MTX treatment after toxicity was sus-pected. This treatment subsequently led to theresolution of the cutaneous ulcerations; however,the highest serum MTX level recorded among ourpatients was 0.07 mol/L, which is less than the 72-hour high-dose toxicity cutoff documented in theliterature. This finding suggests that the serumdrug levels measured during low-dose MTX treat-ment may be of undetermined significance, andinterpretation of toxicity should be based onclinical status.Although cutaneous ulcerations from MTX treat-ment are not life threatening, the pancytopeniacaused by bone marrow suppression can be fatal.4The appearance of eroded psoriatic plaques afterlow-dose MTX has been documented as an indicatorof impending life-threatening pancytopenia andwarrants the rapid cessation of MTX.4,8 All 3 of ourpatients had underlying pancytopenia in addition tocutaneous findings. Additionally, all 3 patients weretreated with numerous antibiotics before a diagnosiswas rendered. Thus, cutaneous ulceration in non-psoriatic patients receiving low-dose MTX warrantsdrug discontinuation and further hematologictesting, especially when the infectious workup isinconclusive.This case series illustrates 3 examples of MTX-induced cutaneous ulceration in nonpsoriatic pa-tients. All 3 patients were women older than 50 yearstaking 15 to 25 mg of MTX per week, who presentedwith cutaneous ulcerations of the extremitiesmistaken for infection. All 3 patients subsequentlyresponded to cessation of MTX and initiation ofleucovorin rescue. In addition, our patients all hadMTX serum levels less than 0.07 mol/L and under-lying pancytopenia. Therefore, this case series sug-gests that cutaneous ulceration caused by low-doseMTX can be suggestive of underlying pancytopeniaand that serum drug levels may be an unreliablemarker of toxicity. This rare cutaneous side effect isan important forewarning for the more severetoxicities of MTX treatment.The authors acknowledge Andras Schaffer, MD, PhD,for his assistance with the dermatopathology in thesecases.REFERENCES1. Kalb RE, Strober B, Weinstein G, Lebwohl M. Methotrexate andpsoriasis: 2009 National Psoriasis Foundation Consensus Con-ference. J Am Acad Dermatol. 2009;60(5):824-837.2. Shiver MB, Hall LA, Conner KB, Brown GE, Cheung WL,Wirges ML. Cutaneous erosions: a herald for impendingpancytopenia in methotrexate toxicity. Dermatology Online J.2014;20(7):5.3. Kurian A, Haber R. Methotrexate-induced cutaneous ulcers in anonpsoriatic patient: case report and review of the literature. JCutan Med Surg. 2011;15(5):275-279.4. Jariwala P, Kumar V, Kothari K, Thakkar S, Umrigar D. Acutemethotrexate toxicity: a fatal condition in two cases ofpsoriasis. Case Rep Dermatol Med. 2014;2014:946716.5. Monch S, Zimmo B, El Helou T, Colmegna I. Methotrexate-in-duced cutaneous erosions. Arthritis & Rheumatol. 2016;68(1):254.6. Delyon J, Ortonne N, Benayoun E, et al. Low-dosemethotrexate-induced skin toxicity: keratinocyte dystrophyas a histologic marker. J Am Acad Dermatol. 2015;73(3):484-490.7. Lennard L. Therapeutic drug monitoring of antimetaboliccytotoxic drugs. Br J Clin Pharmacol. 1999;47(2):131-143.8. Fridlington J, Tripple J, Reichenberg J, Hall C, Diven D. Acutemethotrexate toxicity seen as plaque psoriasis ulceration andnecrosis: a diagnostic clue. Dermatology Online J. 2011;17(11):2.Fig 6. Thin, crusted ulcerations on the medial thighs and an eroded plaque underneath thepannus.JAAD CASE REPORTSVOLUME 3, NUMBER 3Lewis et al 239

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Methotrexate-induced cutaneous ulceration in 3 nonpsoriatic patients: Report of a rare side effect

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