The emergence of rituximab-induced pyoderma gangrenosum: An alert to dermatologists
By Warren R. Heymann, MD, FAAD
Sept. 21, 2022
Vol. 4, No. 38
Recognizing cutaneous adverse drug reactions is medical dermatologist’s forte. This commentary will focus on rituximab-induced pyoderma gangrenosum (RIPG) that characteristically presents as vulvovaginal pyoderma gangrenosum (VVPG) — a condition that I have not encountered (and hope that I never do).
Rituximab is an anti-CD20 chimeric antibody directed against a surface transmembrane protein marker (CD20) expressed on B-cells during differentiation from pre-B-cell until the plasma cell stage, involved in the maturation and activation of B cells. A recent DWI&I commentary focused on late-onset neutropenia due to rituximab. Please see that reference for a discussion of FDA-approved indications and major adverse reactions of rituximab. (1) This discussion is devoted to RIPG. (Please note that the term RIPG is being used loosely, because the precise nature of the association of the drug with pyoderma gangrenosum [PG] is unknown.)
Walsh et al published the first case of VVPG (reported as superficial granulomatous pyoderma [SPG] of the vulva) in a 51-year-old woman who presented with a 6-week history of severe vulvar pain, bleeding, and rapidly progressing ulceration. She had a history of relapsed follicular non-Hodgkin lymphoma and was receiving regular MabThera (rituximab). Clinical and histological findings confirmed a diagnosis of SGP. (2) This was followed by a case series of 4 patients of VVPG who received rituximab for non-Hodgkin lymphoma (NHL). All patients complained of discomfort (pain and/or itch) and discharge (vaginal or anal) and were treated with steroids, immunosuppressants (azathioprine, methotrexate) or IVIG. (3)
Since the publication of these initial reports, several others appeared in the literature, prompting systematic reviews of PG as an adverse event associated with rituximab. Aggarwal sought to determine if a statistically significant signal exists between rituximab and PG in the Food and Drug Administration Adverse Event Reporting System (FAERS). A disproportionality analysis was performed from January 1, 2004 to March 31, 2019, finding 32 cases in which rituximab was administered and PG was reported as an adverse event. A statistically significant signal was supported by 6 reports describing a total of 14 patients who developed VVPG after rituximab administration. Of these 14 patients, 11 had NHL, 1 systemic lupus erythematosus (SLE), 1 rheumatoid arthritis (RA), and 1 granulomatosis with polyangiitis (PGA). (4) In a separate study of the 32 cases identified in FAERS, using a systems biology-informed approach, Hillen et al observed an increased association of PG with rituximab compared with all other medicines; 62.5% were female with a median age of 48 years. The authors found that when stratifying by the indication of the medicines, a signal was observed between PG and rituximab for multiple sclerosis; the association with rituximab and PG was lower in RA and non-Hodgkin’s lymphoma. These findings suggest that the underlying disease may modify the risk of PG. (5) To date, there have been no reports of RIPG in patients with pemphigus.
In their review of 16 cases of new-onset PG following rituximab exposure (presumably many of the same cases identified in the FAERS studies), Croitoru et al noted a mean age of 53.1 years with a marked female predominance (7:1). The mean duration of rituximab exposure before PG onset was 40.9 months. Ulcerative PG was the most prevalent morphology (14/16, 88%). All 14 female cases presented with VVPG. (6)
Spontaneous VVPG is a rare disorder that must be differentiated from other mimickers such as Herpes simplex virus infection, other infections (mycobacterial, fungal, parasitic), Crohn disease, Lipschutz ulcers, vasculitis, or keratinocyte carcinoma. (7,8,9) Drug-induced PG has been reported with interferon and granulocyte-macrophage colony stimulating factor. (10) Targeted therapies including imatinib, sunitinib, adalimumab, and infliximab have also been associated with PG. (11) Interestingly, Breneman et al reported a case of VVPG in a 55-year-old woman treated with ocrelizumab (another anti-CD20 monoclonal antibody) for multiple sclerosis. (12) Klumpp et al detail a case of VVPG in a 23-year-old woman whose multiple sclerosis was treated with ocrelizumab. After discontinuation of the drug, she was treated successfully with IVIG, cyclosporine, and surgical repair. (13)
Notably, many women with rituximab-induced VVPG complain of a profuse vaginal discharge; this was reported in 5 of 6 cases of VVPG presented by Selva-Nayagam et al. (11). Aside from the copious vaginal discharge, rituximab-associated vaginitis may cause vaginal pain and dyspareunia. This diagnosis is rendered once other disorders such as bacterial vaginosis, vulvovaginal candidiasis, herpes simplex, gonorrhea, trichomonas, and chlamydial infections have been excluded. The etiology of rituximab-induced vaginitis is unknown — it is hypothesized that B-cell depletion alters the vaginal microbiome, subsequently contributing to inflammation. (14) The pathomechanism of RIPG demands further scrutiny, but may involve atypical T-cell activation and a neutrophilic response following B-cell depletion and apoptosis. (6). To confound matters further, rituximab has been reported as an effective treatment for recalcitrant cases of PG. (15)
In conclusion, dermatologists must be cognizant of the risk of PG, especially VVPG, in patients on rituximab therapy. Ask women if they have noticed a vaginal discharge (although further study is necessary to determine if this is a prelude to VVPG). Hillen et al state: “As rituximab is an effective treatment in life-threatening and chronic conditions of high morbidity and PG is a treatable condition of rare occurrence, these results do not change the risk/benefit profile of rituximab.” (5) Should RIPG develop, a decision will need to be made on a case-by-case basis if rituximab should be discontinued while treating the PG with standard therapies.
Point to Remember: Rituximab has been increasing reported to induce pyoderma gangrenosum, especially vulvovaginal pyoderma gangrenosum. Dermatologists must be cognizant of this rare complication and its implications.
Our expert’s viewpoint
Kiran Motaparthi, MD, FAAD
Residency Program Director
Director of Dermatopathology
Department of Dermatology
University of Florida College of Medicine
While late-onset neutropenia (LON) may seem to contradict a causative link between rituximab and PG, maturational arrest of neutrophils at the promyelocyte stage could connect both of these complications. (Please see “Early recognition of Rituximab-induced late onset neutropenia is essential.”) The therapeutic mechanism of rituximab may also explain this unique toxicity. Antibody dependent cytotoxicity due to binding of Fcγ and complement dependent cytotoxicity both result in direct activation of neutrophils. Next, cross-presentation of apoptotic B cells by dendritic cells and prolonged B cell lymphopenia can result in T cell activation and dysregulation, respectively. T cells contribute to the pathogenesis of PG through oligoclonal expansion and cytokine signaling. Successful treatment with IVIg is described in multiple reports linking rituximab to VVPG, including those in which corticosteroids failed. IVIg neutralizes antibodies, blocks Fc receptors, inhibits the complement cascade, and regulates dendritic, B, and T cells. (16)
As referenced by Dr. Heymann, another seemingly contradictory clinical finding is the anecdotal efficacy of rituximab for PG, particularly in association with PGA. PG-like lesions are present in more than 25% of patients with PGA, (17) and cANCA (anti-PR3) serology, clinical context and histopathology demonstrating granulomatous vasculitis may be necessary for distinction from classic PG. (18) Unlike RIPG, PG-like lesions associated with PGA and responsive to rituximab are described on the most common anatomic site, the lower extremities. (17, 18, 19, 20)
The potential for RIPG and the fact that rituximab accounts for more than 70% of biologic-induced PG may alarm clinicians. However, RIPG has not been observed following treatment for immunobullous disorders, and idiopathic VVPG is exceptionally rare. Dermatologists should not be dissuaded from prescribing rituximab for pemphigus and BP; instead, they should feel confident that they can recognize a rare complication of rituximab in patients with multiple sclerosis, RA, and NHL owing to its unique clinical presentation.
Heymann WR. Ealy recognition of rituximab-induced late-onset neutropenia is essential. Dermatology World Insights and Inquiries. 2022, Vol 4, No 15. https://www.aad.org/dw/dw-insights-and-inquiries/archive/2022/early-recognition-rituximab-induced-late-onset-neutropenia
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