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Vol. 39. Issue. 1.January - February 2019
Pages 1-110
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Vol. 39. Issue. 1.January - February 2019
Pages 1-110
Case report
DOI: 10.1016/j.nefro.2018.05.005
Open Access
Mycophenolate mofetil-induced mouth ulcers in a kidney transplant patient: Case report and literature review
Úlceras orales secundarias a micofenolato mofetilo en un paciente trasplantado renal: caso clínico y revisión de la literatura
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Adrià Plana-Plaa,
Corresponding author
adriplanapla@gmail.com

Corresponding author.
, Laura Cañas Soléb, Aram Boada Garciaa, Ricardo Lauzurica Valdemorosb
a Department of Dermatology, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain
b Department of Nephrology, Hospital Universitari, Germans Trias i Pujol, Badalona, Barcelona, Spain
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Abstract
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Table 1. Characteristics of the patients included in the study.
Abstract

Mouth ulcers are a cutaneous complication that can often affect kidney transplant patients, mostly due to the effect of immunosuppressive treatment.

Even so, before asserting that said complication is indeed secondary to drugs, it is very important to establish a differential diagnosis with other mouth ulcer causes, such as systemic diseases or viral infections, which are also common in these patients.

Keywords:
Kidney transplant
Mycophenolate mofetil
Mouth ulcers
Cytomegalovirus
Resumen

Las úlceras orales son una de las complicaciones cutáneas que pueden afectar con frecuencia a los pacientes trasplantados renales, debido muchas veces al efecto del tratamiento inmunosupresor.

Aun así, es importante, antes de asegurar que dicha complicación es secundaria a los fármacos, establecer el diagnóstico diferencial con otras causas de úlceras orales como pueden ser enfermedades sistémicas o infecciones virales, también frecuentes en este tipo de pacientes.

Palabras clave:
Trasplante renal
Micofenolato mofetilo
Úlceras orales
Citomegalovirus
Full Text
Introduction

Differential diagnosis of oral ulcers is often difficult, because it covers a large number of disorders. Some infections such as the herpes virus, bullous, autoimmune and hematologic diseases and some malignancies are just a few examples of what may ulcerate the oral mucosa.1 In immunocompromised patients, some unusual disorders, otherwise uncommon in immunocompetent individuals, should also be considered, such as fungal infections, cytomegalovirus (CMV) or drug-induced ulcers. The latter are normally produced by immunosuppressive drugs and are therefore usually seen in polymedicated patients who are susceptible to all kinds of infections, which makes correct diagnosis even more complex.2 Unlike some immunosuppressants, where a higher capacity for resulting in oral ulcers has been demonstrated (mTOR inhibitors are most commonly associated with this type of ulcers), as far as we know, mycophenolate mofetil (MMF) has been noted to rarely cause oral ulcers with only 9 patients reported.1–6

Here we report one new case of MMF-induced oral ulcerations. We also review all patients in the literature with this uncommon side effect.

Report

A 67 year-old man with renal insufficiency due to polycystic kidney disease and arterial hypertension underwent a kidney transplant in 2015. He received immunosupressive treatment with metilprednisolone (5mg/d), tacrolimus (16mg/d) and MMF (2g/d). Nine months after kidney transplantation 3 painful oral ulcers appeared on both sides of the tongue and on the oral mucosa. He also presented intense odynophagia, difficulty swallowing, decreased intake and weight loss without fever. On examination, 2 major aphthous ulcers, with surrounding edema and erythema were present on his tongue (Fig. 1) and 1 smaller erosion was observed in his buccal mucosa (Fig. 2).

Fig. 1.

Clinical photograph shows 2 major aphthous ulcers, with surrounding edema and erythema, on the tongue.

(0.11MB).
Fig. 2.

Clinical photograph shows 1 minor aphthous ulcer, on buccal mucosa.

(0.07MB).

Apart from the immunosupressive treatment, at this moment he was also taking oral valganciclovir because of a CMV infection reactivation. The blood sample test showed leukopenia, anemia and thrombocytopenia with a stable renal function (creatinine 2.2mg/dl) and a normal hepatic profile. Levels of tacrolimus were correct in relation with the time after kidney transplantation.

Cultures of the oral lesions were negative for herpes simplex virus types 1 and 2, CMV, and fungus. Rapid plasma reagin (RPR) and HIV antibody testing results were nonreactive.

Oral biopsy showed nonspecific inflammatory changes on hematoxylin–eosin (H&E) staining. Finally MMF was subsequently discontinued. After 4 days, the patient's oral ulcers decreased considerably in size, with a significant reduction in his oral pain, improving the ability to eat and drink. After 9 days, complete healing of the patient's ulcers was observed. The patient has since remained off MMF with no recurrences of his ulcerations.

Discussion

MMF is a powerful immunosuppressant that is often used to prevent acute rejection in hematopoietic stem cell or solid organ transplant patients as well as in some autoimmune diseases.7,8 Its mechanism of action is based on inhibition of purine synthesis via inhibition of the inosine phosphate dehydrogenase enzyme. This results in a decrease in lymphocyte proliferation that is responsible for the immunosuppressive effects of the drug.7,8 Its most common side effects are digestive in the form of diarrhea or vomiting with extremely varied other adverse effects. Among them, oral ulcers are one of the less frequent and therefore less known by dermatologists.

We searched PubMed with the terms “mycophenolate mofetil” and “oral ulceration” and found 9 cases in the English-language literature. Characteristics of the patients are shown in Table 1.

Table 1.

Characteristics of the patients included in the study.

Study  Year  Age, years  Sex  Transplant type  Time since transplant  Clinical presentation  Histopathology  MMF dose  Concomitant drugs  Outcome after MMF withdrawal 
Salik et al.1  2015  68  Renal  8 months  3 major oral ulcers, sever oral pain  Nonspecific inflammatory changes  2g/d  Tacrolimus (16mg/d)  Healing after 9 days 
Salik et al.1  2015  59  Liver  5 months  2 major and 1 minor oral ulcers, sever oral pain  Nonspecific inflammatory changes  2g/d  Tacrolimus (6mg/d), prednisone (2.5mg/d)  Healing after 4 days 
Salik et al.1  2015  64  Lung  10 months  1 major and 4 minor oral ulcers and sever oral pain  Nonspecific inflammatory changes  1g/d  Ciclosporine (200mg/d), prednisone (40mg/d)  Healing after 7 days 
Philipone et al.2  2014  54  Renal  5 months  1 major and several minor oral ulcers and sever oral pain  Nonspecific inflammatory changes  2g/d  Tacrolimus (16mg/d)  Healing 4 weeks 
Weng et al.3  2011  23  Renal  5 months  Several minor ulcers, gum swelling and sever oral pain  No biopsy was done  2g/d  Ciclosporine (300mg/d), prednisone (12.5mg/d)  Great improvement after 1 week and complete healing after 6 weeks 
Naranjo et al.4  2007  60  Liver  5 days  2 major oral ulcers  No biopsy was done  1g/d  Tacrolimus and prednisone (no doses specified)  Healing after 5 days 
Naranjo et al.4  2007  31  Liver  No specified  2 major oral ulcers  No biopsy was done  1.5g/d  Ciclosporine and metilprednisolone (no doses specified)  Healing after 1 week 
Apostolou et al.5  2004  62  Renal  3 years  1 major and 3 minor oral ulcers and sever oral pain  Nonspecific inflammatory changes  2g/d  Tacrolimus (4mg/d), prednisone (7.5mg/d)  Great improvement after 6 days and complete healing after 6 weeks 
Garrigue6  2001  52  Renal  6 months  Several oral and anal ulcers and sever oral pain  Nonspecific inflammatory changes  2g/d  Ciclosporine (400mg/d), prednisone (10mg/d)  Complete healing after 3 weeks 

MMF, mycophenolate mofetil.

Since the first case reported in 2001, 9 additional cases of MMF-oral ulcerations have been described (including our patient) presenting as very painful ulcers1 (2 or more ulcers per patient), located in the oral mucosa. One case had also anal ulcers and another, edema in gums. To date, all cases published, are in patients who have undergone a solid organ transplant and the dose of MMF that they were receiving, ranged from 1 to 2g/d. In all the cases, the ulcers healed quickly once the drug was stopped. In every reported case improvement of the lesions is observed within the first 4–10 days and complete healing is seen in 6 weeks at most.1–6 Our patient referred significant improvement only four days after stopping the drug. These lesions are usually not accompanied by other side effects and the interval time between starting the drug and the appearance of the ulcers varies greatly, with described cases ranging from 1 week to 3 years.

From the microscopic point of view no specific findings are observed, usually showing nonspecific mixed inflammatory infiltrates with a negative immunofluorescence.1

Despite of this, in our opinion biopsy should always be performed in order to rule out other common diseases such as fungal infections or CMV.

Regarding the pathogenesis of these lesions, most authors propose their appearance as the result of a direct cytotoxic effect of the drug on the mucosa although this point is not yet fully proven.

In conclusion, oral ulcers caused by MMF are a rare cause of oral ulcers that dermatologists should be aware of.

Conflict of interests

The authors declare no conflict of interests.

References
[1]
J. Salik, R. Tang, K. Nord, P.L. Schneirderman, M.E. Grossman.
Mycophenolate mofetil-induced oral ulcerations in solid organ transplant recipients: a report of 3 cases.
JAAD Case Rep, 29 (2015), pp. 261-263
[2]
E. Philipone, A. Rockafellow, R. Sternberg, A. Yoon, D. Koslovsky.
Oral ulcerations as a sequela of tacrolimus and mycophenolate mofetil therapy.
Oral Surg Oral Med Oral Pathol Oral Radiol, 118 (2014), pp. 175-178
[3]
R.R. Weng, C.E. Foster, L.L. Hsieh, P.R. Patel.
Oral ulcers associated with mycophenolate mofetil use in a renal transplant recipient.
Am J Health Syst Pharm, 1 (2011), pp. 585-588
[4]
J. Naranjo, J. Poniachik, D. Cisco, J. Contreras, D. Oksenberg, J.M. Valera, et al.
Oral ulcers produced by mycophenolate mofetil in two liver transplant patients.
Transplant Proc, 39 (2007), pp. 612-614
[5]
T. Apostolou, G. Tsagalis, G. Koutroubas, V. Hadjiconstantinou, S. Drakopoulos.
Mycophenolate mofetil and oral ulcerations.
Transplantation, 27 (2004), pp. 1911-1912
[6]
V. Garrigue, S. Canet, O. Dereure, O. Panabieres, D. Augias, G. Chong, et al.
Oral ulcerations in a renal transplant recipient: a mycophenolate mofetil-induced complication?.
Transplantation, 15 (2001), pp. 968-969
[7]
H.W. Sollinger.
Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group.
Transplantation, 15 (1995), pp. 225-232
[8]
H.W. Sollinger, A.K. Sundberg, G. Leverson, B.J. Voss, J.D. Pirsch.
Mycophenolate mofetil versus enteric-coated mycophenolate sodium: a large, single-center comparison of dose adjustments and outcomes in kidney transplant recipients.
Transplantation, 27 (2010), pp. 446-451
Copyright © 2018. Sociedad Española de Nefrología
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