Targeted therapy with ixekizumab in pyoderma gangrenosum: A case series and a literature overview

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis often associated with underlying systemic immune dysregulation including inflammatory bowel disease (IBD) and internal malignancies.1Patel F. Fitzmaurice S. Duong C. et al.Effective strategies for the management of pyoderma gangrenosum: comprehensive review.Acta Derm Venereol. 2015; 95: 525-531Crossref PubMed Google Scholar It typically presents in patients aged between 22 55 years.1Patel Tender pustules or nodules that are initiated by trauma, called pathergy phenomenon, break down to form necrolytic ulcerations erythematous undermined borders, on lower extremities.1Patel The pathophysiology PG not well understood, but it theorized be an autoreactive response.1Patel An imbalance T helper 17 regulatory cells leads infiltrate along elevated levels tumor necrosis factor-α, interleukin (IL) 1β, IL-1α, IL-8, IL-12, IL-15, IL-17, IL-23, IL-36.2Caproni M. Antiga E. Volpi W. al.The Treg/Th17 cell ratio reduced skin lesions gangrenosum.Br J Dermatol. 173: 275-278Crossref Scopus (53) Scholar,3Ortega-Loayza A.G. Nugent W.H. Lucero O.M. Washington S.L. Nunley J.R. Walsh S.W. Dysregulation gene expression lesional nonlesional 2018; 178: e35-e36Crossref (20) Elevation IL-6, interferon γ, granulocyte colony-stimulating factor, matrix metallopeptidase 9 have also been reported.1Patel Immunostaining ulcer border has demonstrated overexpression proinflammatory cytokine induces differentiation maintenance cells.1Patel In our case series, we report successful treatment extensive targeting IL-17 pathway ixekizumab monotherapy. All initially presented were recruited outpatient dermatology clinic setting (Table I). Treatment was at loading dose 160 mg subcutaneous injection followed 80 every 2 weeks until week 12, then 4 weeks.Table ISummary treated ixekizumabPatientAge (y)SexLocationMedical historyPrior treatmentIxekizumab treatment160MLeft dorsal handMetastatic renal carcinoma cabozantinibTopical corticosteroids12 wk262MRight shin, left calfNo significant medical conditionsNo prior treatment49 wk326FRight calfHidradenitis suppurativa, 6 y prior, SARS-CoV-2Topical intralesional corticosteroids47 wk449FLeft conditionsCyclosporine 18 mo, mycophenolate mofetil over 1 y47 wk, ongoingF, Female; M, male; PG, gangrenosum. Open table new tab F, A 60-year-old man metastatic cabozantinib had 6-month history tender ulcers his hand as previously described group.4Kao A.S. King A.D. Daveluy Successful cabozantinib-induced therapy: report.Dermatol Ther. 2022; 35e15716Crossref (3) ulcerative borders rapidly expanded after biopsy refractory topical corticosteroids (Fig 1, A). Cutaneous malignancy ruled out through biopsy. Cabozantinib discontinued into initiation. improved follow-up assessment 10 B) diminished end 12-week period subsequent discontinuation ixekizumab. No adverse effects noted. 62-year-old without 3 months duration severely painful right shin leg, limiting mobility requiring wheelchair 2). peripheral erythema 2, Biopsy showed neutrophils lymphocytes nuclear dust. Infection excluded gram, periodic acid–Schiff, Grocott's methenamine silver stains. Rapid pain improvement noted initiation B). His nearly resolved 12 49 complete response C D). He remained clear 100 (23 months) follow-up. 26-year-old woman hidradenitis suppurativa episode years ago 1-month papule portion her leg developing same site SARS-CoV-2 infection 3, ulcerated unresponsive tissue culture from bacterial, mycobacterial, fungal infection. Diagnosis made rapid resolution 47 Complete maintained 68 (16 49-year-old calf 5 4). inflammation. fungal, viral cultures. She cyclosporine more than year improvement. At time ixekizumab, she unable work due ulcer. Symptomatic appreciated dosing 4, B-D). patient returned 30 continued weeks. As pathology dysregulation, immunosuppression current mainstay treatment. Topical used treat small, localized lesions. Systemic first-line agents progressive However, multicenter randomized clinical trial 121 less 50% achieved remission either prednisolone cyclosporine.5Ormerod Thomas K.S. Craig F.E. al.Comparison two most commonly treatments results STOP GAP randomised controlled trial.BMJ. 350: h2958Crossref (154) majority experienced least therapy-induced reaction, 66% 68% groups, respectively. Sulfasalazine, tacrolimus, thalidomide, azathioprine, minocycline, methotrexate, clofazimine, mofetil, dapsone monotherapy PG.1Patel Intravenous immunoglobulin efficacious nonpharmacologic option attractive safety profile context active malignancy.1Patel Due concern cost repeated infusion, intravenous generally early subsequently transitioned another medication.1Patel Biologics specific mediators reported safe alternative treatments. Inhibition factor-α infliximab, etanercept, adalimumab effective measure.1Patel Scholar,6Brooklyn T.N. Dunnill M.G. Shetty A. al.Infliximab randomised, double blind, placebo trial.Gut. 2006; 55: 505-509Crossref (481) Skin biopsies shown IL-23A multiple cases.7Guenova Teske Fehrenbacher B. al.Interleukin 23 targeted therapy ustekinumab.Arch 2011; 147: 1203-1205Crossref (135) Scholar,8McPhie M.L. Kirchhof secukinumab: report.SAGE Med Case Rep. 2020; 82050313X20940430Google Ustekinumab, agent plaque psoriasis, yielded outcomes cases effects.9Ye L. Wu Z. Li Zhao X. Wan Wang Off-label uses ustekinumab.Dermatol 35e15910Crossref (1) addition, IL-1 antagonists may treating recalcitrant O’Connor al10O’Connor Gallagher Hollywood Paul O’Connell Anakinra gangrenosum.Clin Exp 2021; 46: 1558-1560Crossref (2) 100% healing anakinra, receptor antagonist blocks activity IL-1α IL-1β, comorbidities. Here, inhibition effects. Other immunomodulating such brodalumab (anti–IL-17R) secukinumab (anti–IL-17A) being proposed available alternatives.1Patel predominance makes inhibiting neutrophil migration promising target. Secukinumab, recombinant human IgG1 monoclonal antibody IL-17A, 50-year-old PG. observed within no recurrence additional therapy.8McPhie Brodalumab, IL-17A antagonist, resolution. 23-year-old acne conglobata, 2-year (Pyoderma gangrenosum, acne, syndrome) corticosteroids, adalimumab, adjuvant methotrexate therapy, month resulted reduction months.11Tee M.W. Avarbock A.B. Ungar J. Frew J.W. therapy.JAAD 6: 1167-1169Abstract Full Text PDF (5) similar outcome seen 52-year-old 10-year recurrent concomitant adalimumab.11Tee mechanism action selective binding IL-17A. benefit avoidance solid malignancy.4Kao Interestingly, paradoxical psoriasis each secukinumab.12Petty A.J. Whitley M.J. Balaban Ellington K. Marano A.L. induced successfully ustekinumab.JAAD 731-733Abstract (9) This suggests intricate interactions yet fully understood. upregulates upstream IL-23 expression, secukinumab-induced ustekinumab therapy.13Fauny Moulin D. D’Amico al.Paradoxical gastrointestinal interleukin-17 blockers.Ann Rheum Dis. 79: 1132-1138Crossref (95) open-labeled, prospective 2018 halted development sepsis patients, complications patients. Reported include exacerbation IBD.13Fauny there risk difference new-onset IBD these comparison meta-analysis trials anti–IL-17 (secukinumab, brodalumab).14Yamada Komaki Y. Micic Sakuraba Systematic review meta-analysis: onset use anti-interleukin-17 agents.Aliment Pharmacol 2019; 50: 373-385Crossref (35) separate retrospective cohort analysis low incidence agents.15Wright Alloo Strunk Garg Real-world among exposed inhibitors.J Am Acad 83: 382-387Abstract (14) Further investigations large biologics still warranted dictate standardized guidelines series demonstrates provides IBD. With favorable compared immunosuppressants, aim raise clinicians’ awareness potential None disclosed.