Rapid resolution of pyoderma gangrenosum with brodalumab therapy

Abstract

Pyoderma gangrenosum (PG) is a burdensome ulcerative dermatosis, which presents in isolation or in association with other inflammatory conditions (eg, inflammatory bowel disease).1Ahn C. Negus D. Huang W. Pyoderma gangrenosum: a review of pathogenesis and treatment.Exp Rev Clin Immunol. 2018; 14: 225-233Crossref PubMed Scopus (64) Google Scholar PG can be therapeutically challenging, especially when first-line treatments (such as oral corticosteroids and cyclosporine) fail to resolve the condition.1Ahn C. Negus D. Huang W. Pyoderma gangrenosum: a review of pathogenesis and treatment.Exp Rev Clin Immunol. 2018; 14: 225-233Crossref PubMed Scopus (64) Google Scholar,2McKenzie F. Cash D. Gupta D. Gupta A. Cummings L.W. Ortega-Loayza A.G. Biologic and small-molecule medications in the management of pyoderma gangrenosum.J Dermatol Treat. 2019; 30: 264-276Crossref PubMed Scopus (16) Google Scholar Although interleukin (IL)-17 and IL-23 antagonism may ameliorate disease activity, only case reports of secukinumab therapy currently exist.2McKenzie F. Cash D. Gupta D. Gupta A. Cummings L.W. Ortega-Loayza A.G. Biologic and small-molecule medications in the management of pyoderma gangrenosum.J Dermatol Treat. 2019; 30: 264-276Crossref PubMed Scopus (16) Google Scholar We report 2 cases of PG that showed rapid resolution in response to brodalumab, 210 mg/1.5 mg, for co-existing hidradenitis suppurativa (HS). Patient 1, a 23-year old man with PASH syndrome (pyoderma gangrenosum, acne conglobata and suppurative hidradenitis) presented with a 24-month history of painful superficial PG on the anterior and posterior surfaces of the lower limbs (Fig 1, A and B). Previous therapy with oral corticosteroids (up to 1 mg/kg/d), adalimumab (40 mg/wk), and adjuvant methotrexate (7.5 mg/wk) (Fig 2, A and B) failed to resolve the ulceration (Fig 1, A and B) and pain (7/10). He enrolled in a clinical trial of brodalumab, 210 mg/1.5 mg subcutaneous weekly, for treatment of HS (NCT04249713).3Frew J.W. Navrazhina K. Sullivan-Whalen M. Gilleaudeau P. Garcet S. Krueger J.G. Weekly administration of brodalumab in hidradenitis suppurativa: an open label cohort study.J Eur Acad Dermatol Venereol. 2020; (In Press)Google Scholar Within 4 weeks, he experienced a rapid reduction in swelling, pain, and re-epithelialization of PG (Fig 1, A and B). Follow-up 6 months after starting brodalumab indicated no recurrence of his PG (Fig 2, B).Fig 2Demographic and disease characteristics of both patients (A) as well as a schematic time course of the disease, previous treatments, and brodalumab therapy (B). Blue lines indicate time and red lines indicate time periods when PG was active. Green lines indicate when brodalumab was actively being administered.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Patient 2, a 52-year-old woman with a 10-year history of recurrent PG of the left anterolateral lower limb (Fig 1, C), was previously treated with intermittent use of oral and intralesional corticosteroids and adalimumab for both PG and coexistent HS (Fig 2, A and B). She started brodalumab, 210 mg/1.5 mL every other week (EOW) as part of a clinical trial for HS (NCT03960268).4Frew J.W. Navrazhina K. Grand D. et al.The effect of subcutaneous brodalumab upon clinical disease activity in hidradenitis suppurativa: an open label cohort study.J Am Acad Dermatol. 2020; 83: 1341-1348Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar No PG was apparent during the course of the clinical trial. After exiting the trial, brodalumab was withheld for 6 weeks when unwell with presumed coronavirus disease 2019, resulting in the development of a rapidly expanding, painful ulceration on the left anterolateral lower limb (Fig 1, C). Recommencement of brodalumab EOW resulted in slow improvement with cyclical increase in pain the week before brodalumab administration. An increase in the frequency of administration of brodalumab was unavailable. Within 12 weeks, the PG had re-epithelialized with minimal residual pain and edema (Fig 1, C). Follow-up 4 months after re-commencement of brodalumab indicated no recurrence of PG (Fig 2, B). The pathophysiology of PG is not completely understood. Dysregulated helper T cell 17/regulatory T cell ratios are observed in lesional tissue1Ahn C. Negus D. Huang W. Pyoderma gangrenosum: a review of pathogenesis and treatment.Exp Rev Clin Immunol. 2018; 14: 225-233Crossref PubMed Scopus (64) Google Scholar,5Caprioni 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: 275-276Crossref PubMed Scopus (49) Google Scholar; however, both improvement and exacerbation with secukinumab (IL-17a antagonist) are reported.2McKenzie F. Cash D. Gupta D. Gupta A. Cummings L.W. Ortega-Loayza A.G. Biologic and small-molecule medications in the management of pyoderma gangrenosum.J Dermatol Treat. 2019; 30: 264-276Crossref PubMed Scopus (16) Google Scholar Brodalumab (IL-17 receptor-A antagonist) is unique in blocking multiple IL-17 isoforms (IL-17A, IL-17C, IL-17F),2McKenzie F. Cash D. Gupta D. Gupta A. Cummings L.W. Ortega-Loayza A.G. Biologic and small-molecule medications in the management of pyoderma gangrenosum.J Dermatol Treat. 2019; 30: 264-276Crossref PubMed Scopus (16) Google Scholar which are upstream regulators of CXCL1 and CXCL8 (IL-8). CXCL1 and CXCL8 (IL-8) are known chemotactic mediators of neutrophils and highly upregulated in PG tissue.1Ahn C. Negus D. Huang W. Pyoderma gangrenosum: a review of pathogenesis and treatment.Exp Rev Clin Immunol. 2018; 14: 225-233Crossref PubMed Scopus (64) Google Scholar This blockade of multiple IL-17 isoforms may contribute to the rapid resolution of PG observed in these cases. Additionally, the high recapture rate of the drug6Lebwohl M. Cather J. Armstrong A. Van Voorhees A. Jacobson A. Recapture rate of brodalumab in patients with a lapse in treatment.J Drugs Dermatol. 2020; 19: 384-387Crossref PubMed Scopus (1) Google Scholar suggests that it is much less likely to result in decreased efficacy if withheld as demonstrated by patient 2. Neither patient had depression or thoughts of self-harm or suicidal ideation and reported their mood was improved due to the rapid decrease in pain from brodalumab therapy. Both patients also showed acceptable control of their HS achieving greater than 75% reduction in the number of inflammatory abscesses and nodules.3Frew J.W. Navrazhina K. Sullivan-Whalen M. Gilleaudeau P. Garcet S. Krueger J.G. Weekly administration of brodalumab in hidradenitis suppurativa: an open label cohort study.J Eur Acad Dermatol Venereol. 2020; (In Press)Google Scholar,4Frew J.W. Navrazhina K. Grand D. et al.The effect of subcutaneous brodalumab upon clinical disease activity in hidradenitis suppurativa: an open label cohort study.J Am Acad Dermatol. 2020; 83: 1341-1348Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar The slower improvement in patient 2 concurs with findings in HS that weekly brodalumab dosing provides more rapid disease control than EOW dosing.3Frew J.W. Navrazhina K. Sullivan-Whalen M. Gilleaudeau P. Garcet S. Krueger J.G. Weekly administration of brodalumab in hidradenitis suppurativa: an open label cohort study.J Eur Acad Dermatol Venereol. 2020; (In Press)Google Scholar This finding may be a result of receptor-mediated clearance by neutrophils (brodalumab binding to neutrophils and removal in the form of pus) in a mechanism similar to that proposed in HS.4Frew J.W. Navrazhina K. Grand D. et al.The effect of subcutaneous brodalumab upon clinical disease activity in hidradenitis suppurativa: an open label cohort study.J Am Acad Dermatol. 2020; 83: 1341-1348Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar Alternatively, brodalumab therapy may be more effective in small lesions or more superficial variants of PG (patient 1) rather than larger ulcerative lesions (patient 2). Although larger placebo-controlled studies and studies in idiopathic PG (without co-existent HS) are needed, these case reports suggest that brodalumab, 210 mg/wk, results in rapid resolution of PG. EOW dosing may also aid resolution of PG; however, resolution is likely to be significantly slower than with weekly dosing.