Letters Amandine Savry, Pharm.D., Ph.D., Senior Pharmacist Florian Correard, Pharmacy Intern Laurence Gauthier Villano, Pharm.D., Senior Pharmacist Oncopharma Unit Pharmacy Department La Timone University Teaching Hospital Assistance Publique—Hôpitaux de Marseille Marseille France Pascale Pisano, Pharm.D., Ph.D., Senior Pharmacist Pharmacology Laboratory Faculty of Pharmacy Aix Marseille University Marseille Bertrand Pourroy, Pharm.D, Ph.D., Senior Pharmacist Oncopharma Unit Pharmacy Department La Timone University Teaching Hospital Assistance Publique—Hôpitaux de Marseille [email protected]

The authors have declared no potential conflicts of interest. DOI 10.2146/ajhp130586

Topical budesonide for severe oral chronic graft-versus-host disease

W

e read with great interest the report by Park et al.1 comparing budesonide and dexamethasone for local treatment of oral chronic graft-versus-host disease (cGVHD). The oral mucosa is a common site of involvement for cGVHD, which can markedly affect daily functioning and quality of life. Therefore, the search for effective treatment for this disease is warranted. The topical approach is desired, since it reduces or eliminates systemic adverse effects and drug interactions. In this respect, budesonide is an ideal agent because it has low bioavailability while possessing a high antiinflammatory potential. This combination results in a pronounced local effect with very low risk for systemic complications. The idea of using topical budesonide for oral cGVHD was supported by early studies2-4 and appeared later in guidelines of the German Countries Bone Marrow Society.5 More recently, a comparative study demonstrated the benefit of budesonide using various dosing protocols.6 The study by Park et al.1 further supports the efficacy of topical budesonide in the treatment of oral cGVHD but had a methodological flaw that obscured budesonide’s superior Continued on page 182

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Letters Continued from page 181

antiinflammatory effect when compared with dexamethasone. The study included patients with all severity levels of oral cGVHD, including those with very low scores (1 or 2) according to National Institutes of Health (NIH) consensus criteria. Patients with NIH scores of 1 or 2 will not be able to fully demonstrate the beneficial effect of corticosteroid treatment, as their tissue has mainly white (lichenoid) changes and little or no erythematous or ulcerative changes. Accordingly, we performed a new statistical analysis of the results reported by Park et al. by first excluding patients with an NIH score of 1 or 2 for oral cGVHD. For the remaining patients, we calculated the mean difference between baseline and posttreatment oral cGVHD scores and applied the Mann–Whitney U-test. This analysis revealed a significantly better response to budesonide than to dexamethasone (p = 0.015). This result contrasts with the authors’ conclusion of no significant difference in efficacy between budesonide and dexamethasone. We believe that the floor effect obscured a significant difference between the efficacy of budesonide and dexamethasone. The addition of our analysis to the results described by Park et al. would suggest that budesonide and dexamethasone are similarly efficacious for mild manifestations of oral cGVHD but that budesonide is more beneficial in more-severe disease. This interpretation and budesonide’s low bioavailability suggest that budesonide is the preferred agent for topical use in oral cGVHD.

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It is worth mentioning that patients with cGVHD are often treated with systemic corticosteroids and immunosuppressive agents and that the former can reduce the severity of oral cGVHD. There is no information in the report by Park et al. about the dosage of systemic corticosteroids changing during the course of the study, so the possible effect of this factor in introducing bias cannot be determined. Further insight should be provided by a large multicenter study that is currently being conducted to compare budesonide with placebo in patients with cGVHD.7 1. Park AR, La HO, Cho BS et al. Comparison of budesonide and dexamethasone for local treatment of oral chronic graft-versushost disease. Am J Health-Syst Pharm. 2013; 70:1383-91. 2. Elad S, Or R, Garfunkel AA, Shapira MY. Budesonide: a novel treatment for oral chronic graft versus host disease. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003; 95:308-11. 3. Sari I, Altuntas F, Kocyigit I et al. The effect of budesonide mouthwash on oral chronic graft versus host disease. Am J Hematol. 2007; 82:349-56. 4. Utsman RA, Epstein JB, Elad S. Budesonide for local therapy of complex oral mucosal immune-mediated inflammatory diseases: case reports. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008; 106:e11-7. 5. Meier JK, Wolff D, Pavletic S et al. Oral chronic graft-versus-host disease: report from the International Consensus Conference on clinical practice in cGVHD. Clin Oral Investig. 2011; 15:127-39. 6. Elad S, Zeevi I, Finke J et al. Improvement in oral chronic graft-versus-host disease with the administration of effervescent tablets of topical budesonide—an open, randomized, multicenter study. Biol Blood Marrow Transplant. 2012; 18:134-40. 7. ClinicalTrials.gov. Efficacy and safety study of budesonide to treat oral chronic

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graft vs host disease (cGvHD). http:// clinicaltrials.gov/show/NCT00887263 (accessed 2013 Nov 7).

Yehuda Zadik, D.M.D., M.H.A., Attending Department of Oral Medicine Hebrew University–Hadassah School of Dental Medicine Jerusalem Israel Idan Nakdimon, B.Sc., Physiologist Israeli Air Force Aero Medical Center Tel Hashomer Israel Cyril Meyerowitz, D.M.D., M.S., Professor and Director Emeritus Eastman Institute for Oral Health University of Rochester Medical Center Rochester, NY Michael Y. Shapira, M.D., Professor Department of Bone Marrow Transplantation and Cancer Immunotherapy Hadassah Hebrew University Medical Center Jerusalem Sharon Elad, D.M.D., M.Sc., Professor and Chair Division of Oral Medicine Eastman Institute for Oral Health University of Rochester Medical Center [email protected]

Dr. Elad is the principal investigator, Dr. Zadik is a coinvestigator, and Dr. Shapira is a site principal investigator for the study cited in their letter as reference 7 (clinicalTrials.gov NCT00887263). The study is sponsored by Dr. Falk Pharma GmbH. The authors have declared no other potential conflicts of interest. DOI 10.2146/ajhp130520

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