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Ustekinumab for Pyoderma Gangrenosum—Reply

Ustekinumab for Pyoderma Gangrenosum—Reply Comments and opinions In reply In response to Kluger's comments on our use of ustekinumab in the treatment of PG,1 we would like to draw attention to several important issues regarding this treatment and its indication in our patient and in general. We agree with Kluger that there is the highest medical need for new and effective treatment options for PG. Various drug regimens have been implemented in the treatment of PG without any of them being effective at all times in all patients. This indicates that different cases of PG as well as the varying efficacy of treatments are likely based at least partly on different disease mechanisms. In addition, many of the drugs used to treat PG (eg, high-dose systemic corticosteroids, cyclosporine, mycophenolate mofetil, thalidomide, cyclophosphamide, infliximab, etanercept) have serious adverse event profiles, increasing the need to choose the right treatment for each patient.2 As medicine has developed, it was understood that the diseases we learned about in our textbooks cannot be interpreted as single entities but rather must be viewed as collections of different diseases that present in similar clinical contexts.3 We are entering the era of personalized or individualized medicine, and to find measures to identify these different disease types is most important. Unfortunately, there is no specific biomarker for PG or PG subtypes available. The diagnosis is predominantly based on the clinical appearance of the disease, and there is no predictive factor that could help physicians choose the best treatment option with the highest likelihood of success in every individual patient.4 Observing elevated IL-23 level in the PG lesion of our patient,1 and having in mind the well-known association of PG with diseases based on an imbalance in favor of the IL-23 and T-helper 17–driven immune response (eg, Morbus Crohn),2 we dared to start a causal treatment directed against IL-12/IL-23p40. The efficacy of this highly specific treatment strongly indicates that IL-23 was at least partially causative for PG in this patient. Assuming that any other treatment could have achieved the same result is highly speculative. In his letter, Kluger especially compares the use of ustekinumab with TNF blocking agents and even suggests that anti-TNF would provide faster healing. We do not think that this discussion is helpful in regard to personalized indication of therapies as in our patient. Moreover, the costs of both drugs are the same, and in regard to the safety profile of TNF blocking agents, the unfortunate experience of infliximab-related septic shock and death in patients with PG has been reported.5,6 In contrast, more than 40 000 records of ustekinumab-treated patients demonstrate an excellent benefit-risk profile of this drug,7,8 especially in comparison with other drugs commonly used in the treatment of PG, after exclusion of severe systemic disease as was excluded in our patient. Last but not least, virtually all treatment options known and available for PG would be considered an off-label use of a drug, at least in Germany. This was explained in detail to our patient as were all available safety data from ustekinumab experiences as well as the well-known difficulty of treating PG. A written informed consent was obtained, and the treatment was conducted in agreement with the principles of the local ethics authorities. We agree, that additional data and, most importantly clinical studies including more patients, will be needed to test the general validity of our concept. Such a clinical trial is currently being organized at our department. Back to top Article Information Correspondence: Dr Guenova, Department of Dermatology, Eberhard Karls University Tübingen, Liebermeisterstrasse 25, 72076 Tübingen, Germany (emmanuella.guenova@med.uni-tuebingen.de). References 1. Guenova E, Teske A, Fehrenbacher B, et al. Interleukin 23 expression in pyoderma gangrenosum and targeted therapy with ustekinumab. Arch Dermatol. 2011;147(10):1203-120521680759PubMedGoogle ScholarCrossref 2. Miller J, Yentzer BA, Clark A, Jorizzo JL, Feldman SR. Pyoderma gangrenosum: a review and update on new therapies. J Am Acad Dermatol. 2010;62(4):646-65420227580PubMedGoogle ScholarCrossref 3. Oro AE. Dermatology in the postgenomic era: harnessing human variation for personalized medicine. Arch Dermatol. 2008;144(3):389-39118347297PubMedGoogle ScholarCrossref 4. Hadi A, Lebwohl M. Clinical features of pyoderma gangrenosum and current diagnostic trends. J Am Acad Dermatol. 2011;64(5):950-95421292348PubMedGoogle ScholarCrossref 5. Wölbing F, Fierlbeck G, Hötzenecker W, Schaller M, Röcken M. Septic shock after treatment of pyoderma gangrenosum with infliximab. Acta Derm Venereol. 2009;89(1):93-9419197554PubMedGoogle Scholar 6. Brooklyn TN, Dunnill MG, Shetty A, et al. Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial. Gut. 2006;55(4):505-50916188920PubMedGoogle ScholarCrossref 7. Lebwohl M, Leonardi C, Griffiths CE, et al. Long-term safety experience of ustekinumab in patients with moderate-to-severe psoriasis (part I of II): results from analyses of general safety parameters from pooled Phase 2 and 3 clinical trials. J Am Acad Dermatol. 2011;(Sep):1721930328PubMedGoogle Scholar 8. Reich K, Leonardi C, Griffiths CM, et al. Update on the cumulative safety experience of ustekinumab: results from the Ustekinumab Psoriasis Clinical Development Program with up to 4 years of follow-up. Paper FC07-03 presented at the 22nd World Congress of Dermatology; May 24-29, 2011; Seoul, South Korea http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Dermatology American Medical Association

Ustekinumab for Pyoderma Gangrenosum—Reply

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References (8)

Publisher
American Medical Association
Copyright
Copyright © 2012 American Medical Association. All Rights Reserved.
ISSN
0003-987X
eISSN
1538-3652
DOI
10.1001/archdermatol.2012.89
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Abstract

Comments and opinions In reply In response to Kluger's comments on our use of ustekinumab in the treatment of PG,1 we would like to draw attention to several important issues regarding this treatment and its indication in our patient and in general. We agree with Kluger that there is the highest medical need for new and effective treatment options for PG. Various drug regimens have been implemented in the treatment of PG without any of them being effective at all times in all patients. This indicates that different cases of PG as well as the varying efficacy of treatments are likely based at least partly on different disease mechanisms. In addition, many of the drugs used to treat PG (eg, high-dose systemic corticosteroids, cyclosporine, mycophenolate mofetil, thalidomide, cyclophosphamide, infliximab, etanercept) have serious adverse event profiles, increasing the need to choose the right treatment for each patient.2 As medicine has developed, it was understood that the diseases we learned about in our textbooks cannot be interpreted as single entities but rather must be viewed as collections of different diseases that present in similar clinical contexts.3 We are entering the era of personalized or individualized medicine, and to find measures to identify these different disease types is most important. Unfortunately, there is no specific biomarker for PG or PG subtypes available. The diagnosis is predominantly based on the clinical appearance of the disease, and there is no predictive factor that could help physicians choose the best treatment option with the highest likelihood of success in every individual patient.4 Observing elevated IL-23 level in the PG lesion of our patient,1 and having in mind the well-known association of PG with diseases based on an imbalance in favor of the IL-23 and T-helper 17–driven immune response (eg, Morbus Crohn),2 we dared to start a causal treatment directed against IL-12/IL-23p40. The efficacy of this highly specific treatment strongly indicates that IL-23 was at least partially causative for PG in this patient. Assuming that any other treatment could have achieved the same result is highly speculative. In his letter, Kluger especially compares the use of ustekinumab with TNF blocking agents and even suggests that anti-TNF would provide faster healing. We do not think that this discussion is helpful in regard to personalized indication of therapies as in our patient. Moreover, the costs of both drugs are the same, and in regard to the safety profile of TNF blocking agents, the unfortunate experience of infliximab-related septic shock and death in patients with PG has been reported.5,6 In contrast, more than 40 000 records of ustekinumab-treated patients demonstrate an excellent benefit-risk profile of this drug,7,8 especially in comparison with other drugs commonly used in the treatment of PG, after exclusion of severe systemic disease as was excluded in our patient. Last but not least, virtually all treatment options known and available for PG would be considered an off-label use of a drug, at least in Germany. This was explained in detail to our patient as were all available safety data from ustekinumab experiences as well as the well-known difficulty of treating PG. A written informed consent was obtained, and the treatment was conducted in agreement with the principles of the local ethics authorities. We agree, that additional data and, most importantly clinical studies including more patients, will be needed to test the general validity of our concept. Such a clinical trial is currently being organized at our department. Back to top Article Information Correspondence: Dr Guenova, Department of Dermatology, Eberhard Karls University Tübingen, Liebermeisterstrasse 25, 72076 Tübingen, Germany (emmanuella.guenova@med.uni-tuebingen.de). References 1. Guenova E, Teske A, Fehrenbacher B, et al. Interleukin 23 expression in pyoderma gangrenosum and targeted therapy with ustekinumab. Arch Dermatol. 2011;147(10):1203-120521680759PubMedGoogle ScholarCrossref 2. Miller J, Yentzer BA, Clark A, Jorizzo JL, Feldman SR. Pyoderma gangrenosum: a review and update on new therapies. J Am Acad Dermatol. 2010;62(4):646-65420227580PubMedGoogle ScholarCrossref 3. Oro AE. Dermatology in the postgenomic era: harnessing human variation for personalized medicine. Arch Dermatol. 2008;144(3):389-39118347297PubMedGoogle ScholarCrossref 4. Hadi A, Lebwohl M. Clinical features of pyoderma gangrenosum and current diagnostic trends. J Am Acad Dermatol. 2011;64(5):950-95421292348PubMedGoogle ScholarCrossref 5. Wölbing F, Fierlbeck G, Hötzenecker W, Schaller M, Röcken M. Septic shock after treatment of pyoderma gangrenosum with infliximab. Acta Derm Venereol. 2009;89(1):93-9419197554PubMedGoogle Scholar 6. Brooklyn TN, Dunnill MG, Shetty A, et al. Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial. Gut. 2006;55(4):505-50916188920PubMedGoogle ScholarCrossref 7. Lebwohl M, Leonardi C, Griffiths CE, et al. Long-term safety experience of ustekinumab in patients with moderate-to-severe psoriasis (part I of II): results from analyses of general safety parameters from pooled Phase 2 and 3 clinical trials. J Am Acad Dermatol. 2011;(Sep):1721930328PubMedGoogle Scholar 8. Reich K, Leonardi C, Griffiths CM, et al. Update on the cumulative safety experience of ustekinumab: results from the Ustekinumab Psoriasis Clinical Development Program with up to 4 years of follow-up. Paper FC07-03 presented at the 22nd World Congress of Dermatology; May 24-29, 2011; Seoul, South Korea

Journal

Archives of Dermatology – American Medical Association

Published: May 1, 2012

Keywords: pyoderma gangrenosum,ustekinumab

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