Clinical manifestations and treatment outcomes of pyoderma gangrenosum following rituximab exposure: A systematic review

To the Editor: Pyoderma gangrenosum (PG) is a highly morbid neutrophilic dermatosis with increasing reports of treatment with rituximab (RTX), a monoclonal antibody targeting CD20.1Alavi A. French L.E. Davis M.D. Brassard A. Kirsner R.S. Pyoderma gangrenosum: an update on pathophysiology, diagnosis and treatment.Am J Clin Dermatol. 2017; 18: 355-372Crossref PubMed Scopus (135) Google Scholar However, the development of PG has also been described in patients receiving RTX therapy.2Al Ghazal P. Dissemond J. Therapy of pyoderma gangrenosum in Germany: results of a survey among wound experts.J Dtsch Dermatol Ges. 2015; 13: 317-324Crossref PubMed Scopus (25) Google Scholar,3Selva-Nayagam P. Fischer G. Hamann I. Sobel J. James C. Rituximab causing deep ulcerative suppurative vaginitis/pyoderma gangrenosum.Curr Infect Dis Rep. 2015; 17: 478Crossref PubMed Scopus (17) Google Scholar A pharmacovigilance analysis of the Food and Drug Administration Adverse Event Reporting System Public Dashboard identified 32 RTX-incident database entries.4Aggarwal P. Pyoderma gangrenosum adverse event with rituximab use: a postmarketing pharmacovigilance analysis.Dermatol Ther. 2020; 33: e13221Crossref PubMed Scopus (4) Google Scholar To better understand the mixed reporting, this systematic review of cases and observational studies aims to describe clinical features and outcomes of patients who developed PG during RTX therapy. The protocol was developed according to Preferred Reporting of Systematic Reviews and Meta-Analyses and registered on PROSPERO (CRD42021239938). In consultation with an education librarian, we searched MEDLINE and EMBASE until June 3, 2021. The inclusion requirements were as follows: (1) development of PG during treatment with RTX; and (2) compatible histology or dermatologist consultation. Of the 173 articles retrieved, 25 duplicates were removed. Based on the title/abstract, 100 articles were further excluded and 48 progressed to full-text review; 11 met the inclusion criteria, with 16 cases included (Supplementary Fig 1; available via Mendeley at https://data.mendeley.com/datasets/6y7bjwtv6h/1). Among the 16 cases of new-onset PG following RTX exposure, the mean age was 53.1 years (standard deviation, 18.3 years), with a marked female predominance (7:1) (Supplementary Table I; available via Mendeley at https://data.mendeley.com/datasets/6y7bjwtv6h/1). The common comorbidities included hematologic malignancy (9/16, 56%) and autoimmune conditions (6/16, 44%). Dosing schedules were mostly regimens of 375 mg/m2 every 3 months or 1000 mg/m2 infusions 2 weeks apart biannually. Six cases reported concomitant immunomodulator use during RTX treatment (6/16, 37.5%). The mean duration of RTX exposure before PG onset was 40.9 months (standard deviation, 36.9 months) (Supplementary Table I). Overall, ulcerative PG was the most prevalent morphology (14/16, 88%). All female cases presented with a vulvovaginal phenotype (14/14, 100%). The commonly utilized systemic treatments for PG were corticosteroids (12/16, 75%) and intravenous immunoglobulins (8/16, 50%). All cases that reported subsequent RTX management indicated discontinuation (12/12, 100% [4/16 not reported]); the majority of discontinued cases achieved a complete response (9/12, 75%) by an average time of 9.7 months (standard deviation, 3.2 months). This review is limited to case reports and series with variable follow-up. However, the cases included reported histology and/or a dermatology consultation (16/16, 100%). On the Naranjo adverse reaction scale, most cases scored “probable” (15/16; Supplementary Table II; available via Mendeley at https://data.mendeley.com/datasets/6y7bjwtv6h/1).5Naranjo C.A. Busto U. Sellers E.M. et al.A method for estimating the probability of adverse drug reactions.Clin Pharmacol Ther. 1981; 30: 239-245Crossref PubMed Scopus (8114) Google Scholar We chose to restrict our reporting to cases of PG that developed following RTX exposure after protocol registration, to highlight this entity. Despite data paucity, there appears to be a clear vulvovaginal site preference for PG in the setting of RTX exposure. According to a study by Selva-Nayagam et al,3Selva-Nayagam P. Fischer G. Hamann I. Sobel J. James C. Rituximab causing deep ulcerative suppurative vaginitis/pyoderma gangrenosum.Curr Infect Dis Rep. 2015; 17: 478Crossref PubMed Scopus (17) Google Scholar vulvovaginal PG is rare; in their review, only 9 cases occurred without RTX exposure between 1995 and 2015.3Selva-Nayagam P. Fischer G. Hamann I. Sobel J. James C. Rituximab causing deep ulcerative suppurative vaginitis/pyoderma gangrenosum.Curr Infect Dis Rep. 2015; 17: 478Crossref PubMed Scopus (17) Google Scholar Furthermore, in our cohort, vulvovaginal PG following RTX exposure was seen across a broad spectrum of associated diseases, both autoimmune and neoplastic, suggesting a true drug association. Mechanistically, the widely variable onset after drug initiation (months to years) may suggest an atypical T-cell activation and neutrophil response to local antigenic stimulation following B-cell depletion and apoptosis; however, the pathogenesis is unknown. Practitioners should consider the association between vulvovaginal PG and RTX in women presenting with genital ulceration and on RTX therapy. Dr Piguet has received honoraria or fees for consulting and/or speaking for AbbVie, Almirall, Celgene, Janssen, Novartis, and Pfizer and has received departmental support for Cardiff University from AbbVie , Almirall , Alliance , Beiersdorf UK Ltd , Biotest , Celgene , Dermal , Eli Lilly , Galderma , Genus Pharma , Globe Micro , Janssen-Celag , La Roche-Posay , L’Oreal , LEO Pharma , Meda , MSD , Novartis , Pfizer , Sinclair Pharma , Spirit , Stiefel , Samumed , Thornton Ross , TyPham , and UCB and for University of Toronto from Sanofi . Drs Croitoru, Sibbald, Alavi, and Zipursky and authors Nathanielsz, Seigel, and Elsawi do not have any conflicts of interest to disclose. The authors thank Julia Martyniuk, an Education Librarian at the Gerstein Science Information Centre, University of Toronto, for providing feedback and consultation regarding their search strategy. DC and VP would like to acknowledge the Canadian Dermatology Foundation for a grant on the study of pyoderma gangrenosum.