established for the induction and maintenance of remission from paradoxical psoriasis in the setting of uncontrolled underlying disease while maintaining anti-TNF therapy.18,19
Secukinumab has been used to treat recalcitrant anti-TNF induced psoriasis, but is not typically a first-line agent.16 As an IL-17 inhibitor, it is suited to treat both psoriasis and anti-TNFinduced psoriasis, which evidently must also be mediated by IL-17 producing Th17 cells.20 In addition to secukinumab’s efficacy in psoriasis, its mechanism of action is also implicated in PG treatment, as IL-17 mediates neutrophil migration and homeostasis.21,22 Additionally, IL-17 and its receptor are overexpressed in PG lesions and a greater ratio of IL-17-producing Th17 cells is seen in PG patients.23 For these reasons, IL-17 targeted therapy in PG has already been suggested.24,25
In our case, secukinumab was initiated for anti-TNF-induced psoriasis with the hope of also controlling the patient’s PG. In the end, while secukinumab induced remission of psoriasis, it only temporarily alleviated PG symptoms. One possible reason for this failure is that PG pathophysiology does not solely rely on IL-17 signaling and other inflammatory pathways are likely involved. Towards this end, new investigations of PG-associated conditions suggest it to be a disease of the innate immune system in which inflammasomes activate IL-8.1 As a result, IL-17 therapy may not be sufficient for all cases of PG.
Lastly, we examine methotrexate, a folate antimetabolite and dihydrofolate reductase inhibitor. It is a commonly cited systemic agent used to induce remission of mild to severe psoriasis as well as in anti-TNF-induced psoriasis.16,26 Our case demonstrates that as an adjunctive medication, methotrexate can effectively prevent the development of anti-TNF-induced psoriasis in a patient with a history of this paradoxical reaction.
Secukinumab has been used to treat recalcitrant anti-TNF induced psoriasis, but is not typically a first-line agent.16 As an IL-17 inhibitor, it is suited to treat both psoriasis and anti-TNFinduced psoriasis, which evidently must also be mediated by IL-17 producing Th17 cells.20 In addition to secukinumab’s efficacy in psoriasis, its mechanism of action is also implicated in PG treatment, as IL-17 mediates neutrophil migration and homeostasis.21,22 Additionally, IL-17 and its receptor are overexpressed in PG lesions and a greater ratio of IL-17-producing Th17 cells is seen in PG patients.23 For these reasons, IL-17 targeted therapy in PG has already been suggested.24,25
In our case, secukinumab was initiated for anti-TNF-induced psoriasis with the hope of also controlling the patient’s PG. In the end, while secukinumab induced remission of psoriasis, it only temporarily alleviated PG symptoms. One possible reason for this failure is that PG pathophysiology does not solely rely on IL-17 signaling and other inflammatory pathways are likely involved. Towards this end, new investigations of PG-associated conditions suggest it to be a disease of the innate immune system in which inflammasomes activate IL-8.1 As a result, IL-17 therapy may not be sufficient for all cases of PG.
Lastly, we examine methotrexate, a folate antimetabolite and dihydrofolate reductase inhibitor. It is a commonly cited systemic agent used to induce remission of mild to severe psoriasis as well as in anti-TNF-induced psoriasis.16,26 Our case demonstrates that as an adjunctive medication, methotrexate can effectively prevent the development of anti-TNF-induced psoriasis in a patient with a history of this paradoxical reaction.
CONCLUSION
Anti-TNF-induced psoriasiform lesions fully remit with adjunct
secukinumab therapy despite continuation of anti-TNF therapy.
These lesions stay in remission with adjunct methotrexate therapy.
DISCLOSURES
All authors have no relevant conflicts of interest to disclose.
REFERENCES
1. Ahn C, Negus D, Huang W. Pyoderma gangrenosum: a review of pathogenesis and treatment. Expert Rev Clin Immunol. 2018;14(3):225-233.
2. Wang EA, Steel A, Luxardi G, et al. Classic ulcerative pyoderma gangrenosum is a T cell-mediated disease targeting follicular adnexal structures: a hypothesis based on molecular and clinicopathologic studies. Front Immunol. 2017;8:1980.
3. Maverakis E, Goodarzi H, Wehrli LN, Ono Y, Garcia MS. The etiology of paraneoplastic autoimmunity. Clin Rev Allergy Immunol. 2012;42(2):135-144.
4. Wang EA, Maverakis E. The rapidly evolving lesions of ulcerative pyoderma gangrenosum: a timeline. Int J Dermatol. 2018;57(8):983-984.
5. Sharon V, Burrall B, Patel F, et al. Multimodal therapy of idiopathic pyoderma gangrenosum. Dermatol Online J. 2014;20(6).
6. Langan SM, Groves RW, Card TR, Gulliford MC. Incidence, mortality, and disease associations of pyoderma gangrenosum in the United Kingdom: a retrospective cohort study. J Invest Dermatol. 2012;132(9):2166-2170.
7. Le ST, Wang JZ, Alexanian C, et al. Peristomal pyoderma gangrenosum: An exceedingly rare and overdiagnosed entity? J Am Acad Dermatol. 2019;81(1):e15.
8. Maverakis E, Ma C, Shinkai K, et al. Diagnostic criteria of ulcerative pyoderma gangrenosum: a Delphi consensus of international experts. JAMA Dermatol. 2018;154(4):461-466.
9. Maverakis E, Le ST, Callen J, et al. New validated diagnostic criteria for pyoderma gangrenosum. J Am Acad Dermatol. 2019;80(4):e87-e88.
10. Partridge ACR, Bai JW, Rosen CF, Walsh SR, Gulliver WP, Fleming P. Effectiveness of systemic treatments for pyoderma gangrenosum: a systematic review of observational studies and clinical trials. Br J Dermatol. 2018;179(2):290-295.
11. Patel F, Fitzmaurice S, Duong C, et al. Effective strategies for the management of pyoderma gangrenosum: a comprehensive review. Acta Derm Venereol. 2015;95(5):525-531.
12. Brooklyn TN, Dunnill MGS, Shetty A, et al. Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial. Gut. 2006;55(4):505-509.
13. Sivamani RK, Goodarzi H, Garcia MS, et al. Biologic therapies in the treatment of psoriasis: a comprehensive evidence-based basic science and clinical review and a practical guide to tuberculosis monitoring. Clin Rev Allergy Immunol. 2013;44(2):121-140.
14. Hellstrom AE, Farkkila M, Kolho KL. Infliximab-induced skin manifestations in patients with inflammatory bowel disease. Scandinavian journal of gastroenterology. 2016;51(5):563-571.
15. Wollina U, Hansel G, Koch A, Schönlebe J, Köstler E, Haroske G. Tumor necrosis factor-α inhibitor-induced psoriasis or psoriasiform exanthemata. Am J Clin Dermatol. 2008;9(1):1-14.
16. Li SJ, Perez-Chada LM, Merola JF. TNF inhibitor-induced psoriasis: proposed algorithm for treatment and management. Journal of Psoriasis and Psoriatic Arthritis. 2018;4(2):70-80.
17. Denadai R, Teixeira FV, Steinwurz F, Romiti R, Saad-Hossne R. Induction or exacerbation of psoriatic lesions during anti-TNF-α therapy for inflammatory bowel disease: A systematic literature review based on 222 cases. J Crohns Colitis. 2013;7(7):517-524.
18. Kirkham B, Mease PJ, Nash P, et al. AB0945 Secukinumab efficacy in patients with active psoriatic arthritis: pooled analysis of four phase 3 trials by prior anti-tnf therapy and concomitant methotrexate use. Ann Rheum Dis. 2018;77(Suppl 2):1597.
19. Farhangian ME, Feldman SR. Immunogenicity of biologic treatments for psoriasis: therapeutic consequences and the potential value of concomitant methotrexate. Am J Clin Dermatol. 2015;16(4):285-294.
20. Yiu ZZ, Griffiths CE. Interleukin 17-A inhibition in the treatment of psoriasis. Expert Rev Clin Immunol. 2016;12(1):1-4.
21. Krstic A, Mojsilovic S, Jovcic G, Bugarski D. The potential of interleukin-17 to mediate hematopoietic response. Immunol Res. 2012;52(1-2):34-41.
22. Ye P, Rodriguez FH, Kanaly S, et al. Requirement of interleukin 17 receptor signaling for lung Cxc chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. Int J Clin Exp Med. 2001;194(4):519-528.
23. Marzano AV, Fanoni D, Antiga E, et al. Expression of cytokines, chemokines and other effector molecules in two prototypic autoinflammatory skin diseases, pyoderma gangrenosum and Sweet's syndrome. Clin Exp Immunol. 2014;178(1):48-56.
24. Goodarzi H, Sivamani RK, Garcia MS, et al. Effective strategies for the management of pyoderma gangrenosum. Adv Wound Care. 2012;1(5):194-199.
25. Caproni M, Antiga E, Volpi W, et al. The Treg/Th17 cell ratio is reduced in the skin lesions of patients with pyoderma gangrenosum. Br J Dermatol. 2015;173(1):275-278.
26. Haustein UF, Rytter M. Methotrexate in psoriasis: 26 years' experience with low-dose long-term treatment. J Eur Acad Dermatol Venereol. 2000;14(5):382-388.
2. Wang EA, Steel A, Luxardi G, et al. Classic ulcerative pyoderma gangrenosum is a T cell-mediated disease targeting follicular adnexal structures: a hypothesis based on molecular and clinicopathologic studies. Front Immunol. 2017;8:1980.
3. Maverakis E, Goodarzi H, Wehrli LN, Ono Y, Garcia MS. The etiology of paraneoplastic autoimmunity. Clin Rev Allergy Immunol. 2012;42(2):135-144.
4. Wang EA, Maverakis E. The rapidly evolving lesions of ulcerative pyoderma gangrenosum: a timeline. Int J Dermatol. 2018;57(8):983-984.
5. Sharon V, Burrall B, Patel F, et al. Multimodal therapy of idiopathic pyoderma gangrenosum. Dermatol Online J. 2014;20(6).
6. Langan SM, Groves RW, Card TR, Gulliford MC. Incidence, mortality, and disease associations of pyoderma gangrenosum in the United Kingdom: a retrospective cohort study. J Invest Dermatol. 2012;132(9):2166-2170.
7. Le ST, Wang JZ, Alexanian C, et al. Peristomal pyoderma gangrenosum: An exceedingly rare and overdiagnosed entity? J Am Acad Dermatol. 2019;81(1):e15.
8. Maverakis E, Ma C, Shinkai K, et al. Diagnostic criteria of ulcerative pyoderma gangrenosum: a Delphi consensus of international experts. JAMA Dermatol. 2018;154(4):461-466.
9. Maverakis E, Le ST, Callen J, et al. New validated diagnostic criteria for pyoderma gangrenosum. J Am Acad Dermatol. 2019;80(4):e87-e88.
10. Partridge ACR, Bai JW, Rosen CF, Walsh SR, Gulliver WP, Fleming P. Effectiveness of systemic treatments for pyoderma gangrenosum: a systematic review of observational studies and clinical trials. Br J Dermatol. 2018;179(2):290-295.
11. Patel F, Fitzmaurice S, Duong C, et al. Effective strategies for the management of pyoderma gangrenosum: a comprehensive review. Acta Derm Venereol. 2015;95(5):525-531.
12. Brooklyn TN, Dunnill MGS, Shetty A, et al. Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebo controlled trial. Gut. 2006;55(4):505-509.
13. Sivamani RK, Goodarzi H, Garcia MS, et al. Biologic therapies in the treatment of psoriasis: a comprehensive evidence-based basic science and clinical review and a practical guide to tuberculosis monitoring. Clin Rev Allergy Immunol. 2013;44(2):121-140.
14. Hellstrom AE, Farkkila M, Kolho KL. Infliximab-induced skin manifestations in patients with inflammatory bowel disease. Scandinavian journal of gastroenterology. 2016;51(5):563-571.
15. Wollina U, Hansel G, Koch A, Schönlebe J, Köstler E, Haroske G. Tumor necrosis factor-α inhibitor-induced psoriasis or psoriasiform exanthemata. Am J Clin Dermatol. 2008;9(1):1-14.
16. Li SJ, Perez-Chada LM, Merola JF. TNF inhibitor-induced psoriasis: proposed algorithm for treatment and management. Journal of Psoriasis and Psoriatic Arthritis. 2018;4(2):70-80.
17. Denadai R, Teixeira FV, Steinwurz F, Romiti R, Saad-Hossne R. Induction or exacerbation of psoriatic lesions during anti-TNF-α therapy for inflammatory bowel disease: A systematic literature review based on 222 cases. J Crohns Colitis. 2013;7(7):517-524.
18. Kirkham B, Mease PJ, Nash P, et al. AB0945 Secukinumab efficacy in patients with active psoriatic arthritis: pooled analysis of four phase 3 trials by prior anti-tnf therapy and concomitant methotrexate use. Ann Rheum Dis. 2018;77(Suppl 2):1597.
19. Farhangian ME, Feldman SR. Immunogenicity of biologic treatments for psoriasis: therapeutic consequences and the potential value of concomitant methotrexate. Am J Clin Dermatol. 2015;16(4):285-294.
20. Yiu ZZ, Griffiths CE. Interleukin 17-A inhibition in the treatment of psoriasis. Expert Rev Clin Immunol. 2016;12(1):1-4.
21. Krstic A, Mojsilovic S, Jovcic G, Bugarski D. The potential of interleukin-17 to mediate hematopoietic response. Immunol Res. 2012;52(1-2):34-41.
22. Ye P, Rodriguez FH, Kanaly S, et al. Requirement of interleukin 17 receptor signaling for lung Cxc chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. Int J Clin Exp Med. 2001;194(4):519-528.
23. Marzano AV, Fanoni D, Antiga E, et al. Expression of cytokines, chemokines and other effector molecules in two prototypic autoinflammatory skin diseases, pyoderma gangrenosum and Sweet's syndrome. Clin Exp Immunol. 2014;178(1):48-56.
24. Goodarzi H, Sivamani RK, Garcia MS, et al. Effective strategies for the management of pyoderma gangrenosum. Adv Wound Care. 2012;1(5):194-199.
25. Caproni M, Antiga E, Volpi W, et al. The Treg/Th17 cell ratio is reduced in the skin lesions of patients with pyoderma gangrenosum. Br J Dermatol. 2015;173(1):275-278.
26. Haustein UF, Rytter M. Methotrexate in psoriasis: 26 years' experience with low-dose long-term treatment. J Eur Acad Dermatol Venereol. 2000;14(5):382-388.
AUTHOR CORRESPONDENCE
Emanual Maverakis MD emaverakis@ucdavis.edu
