Curr Infect Dis Rep (2015) 17:23 DOI 10.1007/s11908-015-0478-5
GENITOURINARY INFECTIONS (J SOBEL, SECTION EDITOR)
Rituximab Causing Deep Ulcerative Suppurative Vaginitis/Pyoderma Gangrenosum Priya Selva-Nayagam & Gayle Fischer & Ian Hamann & Jack Sobel & Craig James
# Springer Science+Business Media New York 2015
Abstract Pyoderma gangrenosum (PG) is a rare cause of purulent vulvovaginal ulceration. Six recent cases of vulvovaginal pyoderma gangrenosum associated with rituximab are described. All cases were seen in the setting of rituximab used for the treatment of B cell non Hodgkin’s lymphoma (NHL). Age range was 50–74; symptoms were present for 2–24 months and severe pain, heavy discharge and large, deep purulent ulcers extending into the vagina were seen. This ar-
ticle reviews previous reports of vulvovaginal pyoderma gangrenosum, discusses important differential diagnoses in this setting, and provides evidence supporting rituximab as the cause of pyoderma gangrenosum in this cohort. Keywords Vulvovaginal pyoderma gangrenosum . Rituximab . Vulvovaginal ulceration . Intravenous immunoglobulin . Non Hodgkin’s lymphoma . Neutrophilic dermatosis . Pyoderma gangrenosum . Rituximab complications . Vulvovaginal discharge
This article is part of the Topical Collection on Genitourinary Infections P. Selva-Nayagam (*) Department of Dermatology, Queen Elizabeth Hospital, Adelaide, Australia e-mail: [email protected] P. Selva-Nayagam Department of Gynecology, Royal Adelaide Hospital, Adelaide, Australia G. Fischer Department of Dermatology, Royal North Shore Hospital, Sydney, Australia G. Fischer The University of Sydney, Sydney, Australia I. Hamann Mid North Coast Dermatology, Port Macquarie, Australia I. Hamann The Department of Dermatology, Westmead Hospital, Sydney, Australia J. Sobel Department of Internal Medicine, School of Medicine, Wayne State University, Detroit, MI, USA C. James Adelaide Pathology Partners, Adelaide, Australia
Introduction Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody. It is directed against the CD20 antigen, found on the surface of normal and malignant B lymphocytes. It was the first monoclonal antibody developed as a specific cancer agent, and was approved in 1997 for the treatment of low-grade B cell non Hodgkin lymphoma (NHL) [1]. Since that time, its therapeutic use has expanded significantly to other B cell malignancies and a large number of autoimmune diseases. In 2010, its sales were estimated to be in excess of $US6.8 billion worldwide [1]. Deep, purulent, vulvovaginal ulceration suggests consideration of an infective or inflammatory process. The latter includes non sexually acquired acute genital ulceration (NSAG U), Behcet’s syndrome, Crohn’s disease and pyoderma gangrenosum (PG). PG is an inflammatory, ulcerative, chronic dermatosis of unknown aetiology [2]. The diagnosis is based on clinical features, exclusion of other infective/non infective causes of ulceration and presence of associated diseases [3]. We recently published a series of four women who developed deep,
23
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purulent vulvovaginal ulceration in the setting of rituximab therapy for B cell NHL [4]. One previous case has been documented in the literature [5], and we have seen a further sixth case recently. We describe the clinical features of these cases and highlight the association with rituximab.
Materials, Methods and Results The case notes of our five cases were reviewed and a literature search was undertaken using the criteria ‘Rituximab and vulvovaginal Pyoderma Gangrenosum’. The clinical features, investigations and treatment of five of ours, and the one previous case report in the literature are summarised in Table 1. A literature search was also conducted for vulvovaginal PG and genital PG in the last 20 years, and the nine other reported cases with vulvovaginal PG are summarised in Table 2. All six Rituximab related patients were treated with this for B cell NHL, three had additional cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone (CHOP) and two cyclophosphamide, vincristine and prednisone (CVP). The age range of women was 50–74 years; average 59 years. All patients complained of severe pain, and four of six also had heavy discharge. Duration of symptoms ranged from 1.5 to 24 months, average 10 months. Large, deep purulent vulvar ulcers were observed in all patients and five of six patients also suffered extensive involvement of the vagina (Fig. 1). All patients with a heavy discharge had significant vaginal involvement and a longer duration of symptoms (average Table 1
11 months compared to 1.5). There was no history of fever typically associated with NSAGU prodrome. Two patients (case 1 and 3) had abdominal and perianal symptoms with anal inflammation, mucous discharge and perianal ulcer. Both patients underwent endoscopy and colonoscopy with negative findings whilst one (case 1) had anoscopy and biopsy confirming involvement of the anal canal with PG. Two patients (case 1 and 2) had crater-like holes suggesting an underlying fistulous tract (Fig. 1). MRI in these patients revealed a tract in one heading from the vulva towards the anus, and a fistula in another extending to the anus. Two patients (case 1 and 2) had urinary symptoms of severe frequency and urgency. Cystoscopy revealed chronic cystitis in one (case 1) and was normal in the other (case 2). The chronic cystitis case was associated with CMV and BK virus infection, and improved following treatment with intravesical ganciclovir. Her immunosuppression was ceased and treatment changed to intravenous immunoglobulin (IVIG). The bladder symptoms of case 2 improved and cleared with treatment of the PG. All patients had repeated negative vulvar cultures and histopathology consistent with PG. Two patients (case 1 and 3) developed hypogammaglobulineamia, a well-described side effect of rituximab [6]. All six cases responded to immunosuppression or IVIG therapy plus withdrawal of rituximab, with complete healing of ulcers. Azathioprine and prednisolone were used in case 1 and 3. Both cases were changed to IVIG 2 g/kg monthly infusions
Presentation, clinical features and treatment of six cases with PG associated with rituximab
Pt. no/age
Initial diagnosis
Treatment
Vulvovaginal symptoms
Treatment for PG
1/62
NHL
R-CHOP
Prednisolone, azathioprine, good response, changed to IVIG with diagnosis of CMV and BKvirus cystitis
2/50
NHL
3/56
NHL
R-CHOP followed by 3-monthly rituximab 3-monthly rituximab
4/60
NHL
3-monthly rituximab
8 months of pain, discharge, deep vulvar ulceration, perianal mucous discharge, irritation and diarrhoea. Severe urinary frequency and urgency 14 months itch, discharge, discomfort, pain. Urinary frequency and urgency 5 months of heavy discharge, followed by painful ulceration. Intermittent diarrhoea. Jan 2011—dysuria, vaginal burning, heavy discharge
5/74
NHL, autoimmune haemolytic anaemia NHL
Rituximab and IVIG infusions 2–3 monthly
2 years severe purulent discharge, deep vulvar ulcers
CHOP 2003, relapse in 2007, R-CVP Ongoing 3 monthly rituximab infusions
6 weeks pain, bleeding, rapidly progressing ulceration
6/51 [5]
Prednisolone, IVIG
Prednisolone and azathioprine, no response, changed to IVIG Varying doses of prednisolone, which patient did not tolerate (insomnia). High-dose methotrexate (30 mg/week) led to resolution 10 % hydrocortisone cream, intra-vaginal and on vulva daily. Ongoing daily intravaginal hydrocortisone cream as maintenance Prednisolone and minocycline
Curr Infect Dis Rep (2015) 17:23
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Table 2
Nine reported cases of vulvovaginal PG unrelated to rituximab
Case no/age citation
Presentation
OE
Associated conditions
Treatment
1/74 [3] 2/47 [7] 3/29 [8] 4/44 [9] 5/19 [10] 6/73 [11] 7/44 [12] 8/10 [13] 9/55 [14]
Painful vulvar ulcer 2 years
Nil
Rapid onset painful vulvar and vaginal ulcer Breakdown of obstetric laceration, painful and expanding over 6 weeks Large vulvar ulcer
Deep large vulvar ulcer covered in yellow material Large vaginal and perineal ulcer with yellow slough Large deep ulcer involving labia on R side extending to clitoris Large ulcer involving r side vulva
Prednisolone 20 mg/day Colchicine, changed to prednisolone 15 mg/day Cyclosporine
Collagenous colitis
2 months of pain
2.5-cm ulcer R lower labia majora
Nil
Cyclosporine + topical tacrolimus Prednisolone 30 mg/day
6 weeks of vulvar pain
Large and multiple ulcers with adherent slough Large deep sloughy ulcers
MDS
Prednisolone 50 mg/day
Crohn’s disease
Cyclosporine
L labial ulcer with raised tender, undermined border Deep ulceration of the vulva, vagina and the R gluteal region
Nil
Cyclosporine 3.5 mg/kg and prednisolone 10 mg/day Cyclosporine 5 mg/kg/day
Rapid onset of painful ulceration Painful pustule, which rapidly evolved into an ulcer Rapidly progressing painful redness and infiltration of the skin, followed by necrotisation
once CMV and BK virus was discovered in case 1 and due to poor response in case 3. Case 2 was treated with prednisolone for rapid response followed by high-dose IVIG monthly. Case 4 responded to high-dose (30 mg weekly) oral methotrexate, case 5 cleared with topical and intra-vaginal hydrocortisone 10 % cream and case 6 prednisolone and minocycline. IVIG was considered ideal treatment given the hypo-gammaglobulineamia in two patients and increased risk of lymphoma recurrence with immunosuppression. Case 1–5 cleared completely of their ulcers and discharge. Case 1 and 4 have remained free of their disease on no treatment with 6 months follow-up. Case 2 and 3 had a recurrence of their vaginal discharge, bladder and bowel symptoms, respectively, 7 and 9 months after IVIG was ceased and have required further IVIG infusions with good
Myelodysplastic syndrome (MDS). Nil
Nil
response. Case 5 has required ongoing intra-vaginal hydrocortisone daily for control of the discharge. Repeat challenge with rituximab has not been necessary. No further information is available on case 6. Nine other cases of vulvovaginal PG have been reported in the literature in the last 20 years (Table 2) [3, 7–14]. The age range was 10–68 years; average 43 years. The duration of symptoms was shorter compared to our series, with all but two claiming symptoms for less than 30 days. This series included a solitary child aged 10 years (case 8). This patient had preceding fever and lymphadenopathy, no associated systemic disease and apparent short-duration vulvar ulceration. This raises the possibility of NSAGU. All reported patients underwent immunosuppression treatment with clearance of ulcers; four of nine had underlying systemic disease (myelodysplastic syndrome 2 and inflammatory bowel disease 2).
Discussion
Fig 1 Extensive deep purulent ulceration extending into the vagina with a heavy discharge. Arrow, crater-like hole
Pyoderma gangrenosum is a rare, deep ulcerating, neutrophilic dermatosis [15]. The presentation of a patient with painful purulent vulvar ulcers generates a large list of potential differential diagnoses. Infections, malignancy, vascular disease, drugs, vasculitis, exogenous injury, Behcet’s disease, NSAGU and other neutrophilic dermatoses need to be excluded before designation as pyoderma gangrenosum [3]. Helpful clinical features for PG include site (usually lower limbs), pathergy, associated systemic disease, follicular-based pustules as the
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initial lesion, heavy purulent discharge, undermined violaceous border and crater-like holes with cribriform scarring in healed lesions. Crater-like holes refer to openings of fistulous tracts from which pus can be expressed on applying pressure. This is regarded as an important sign for PG. The histopathology of PG is non specific, and biopsy is predominantly employed to exclude other differential diagnoses [3]. Despite these difficulties, diagnostic criteria for PG have been proposed. Diagnosis requires both major criteria and at least two minor criteria. Major criteria: 1. Rapid progression of a painful, necrolytic, cutaneous ulcer with an irregular, violaceous and undermined border. 2. Other causes of cutaneous ulceration have been excluded. Minor criteria: 1. History suggestive of pathergy, or clinical finding of cribriform scarring. 2. Systemic diseases associated with PG. 3. Histopathologic findings (sterile dermal neutrophilia, ± mixed inflammation, ± lymphocytic vasculitis), 4. Rapid response’ to immunosuppressive treatment [16]. All six cases of vulvar PG in the setting of rituximab and B cell NHL developed large painful ulcers over months to years with ragged irregular borders. A profuse heavy discharge was seen in four of six patients, histology was consistent with PG and cultures were negative. A rapid response to immunosuppression/ IVIG therapy was characteristic of all our cases. Non sexually acquired acute genital ulceration (NSAGU) is similar in its non infective findings and non specific histology. The clinical features, however, are significantly different. NSAGU ulcers are well demarcated and although occasionally can be large and painful, appear self limiting [17, 18]. They affect young adolescent girls with no underlying systemic disease. In contrast, our youngest patient was 50. All had large poorly demarcated and persistent ulcers, lasting months to years with no tendency to spontaneous healing. Two of our patients also had crater-like holes (case 1 and 2) with fistulous tracts (Fig. 2). PG lesions in adults most commonly affect the lower limbs [15], and involvement of vulvar skin is rare. Apart from the described six cases, only nine previous cases have been reported in the literature over the past 20 years. Of these, 44 % (four of nine) had associated underlying disease, which is similar to other reported series of PG. Two cases had myelodysplastic
Fig 2 a Case 5 presentation, showing inflammation oedema, heavy purulent discharge and deep ulceration. b Case 5 healed following treatment, showing clearance but with scarring typically seen in PG
Curr Infect Dis Rep (2015) 17:23
syndrome, but there were no cases with NHL or use of rituximab. By contrast, all six cases described in this paper had an association with B cell systemic non Hodgkin’s lymphoma. Underlying haematologic malignancy is an uncommon but well-described association with PG. A recent comprehensive review of all published series of PG suggested an incidence of approximately 5 % [15]. Of the 35 patients with haematologic malignancy, leukaemia was the most commonly reported in 13 patients, whilst B cell non Hodgkin’s lymphoma has been reported in only 1 case. The treatment regime in this lymphomaassociated case was not disclosed. A PubMed search of the last 20 years using the terms ‘Non Hodgkin Lymphoma and PG’ revealed a solitary case report with B cell lymphoma [19]. This patient was also treated with rituximab (and CHOP) prior to his PG developing as a pathergic lesion at a syringe driver site on his arm. PG is an inflammatory skin condition included in the spectrum of neutrophilic and auto-inflammatory syndromes [20]. Although the neutrophils seen on histopathology of PG appear morphologically normal, a number of studies have demonstrated functional abnormality of these cells [15]. [21] The importance of neutrophils in PG is also illustrated by the precipitation of the disease by granulocyte colony stimulating factor (GCSF) [21]. Rituximab acts on neutrophils in several ways. Late onset neutropenia (LON) occurring post 4 weeks after rituximab therapy appears in 5–27 % of lymphoma patients. This is thought to be a result of maturation arrest at the promyelocyte stage in the bone marrow [22]. Rituximab induces apoptosis, antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) [23]. Both complement activation and antibody binding via FCγ receptor results in direct activation of neutrophils [23]. A recent study has suggested that neutrophils are also important in direct apoptosis of lymphoma cells by rituximab via cross-linking of the FcRIIIb receptor on these cells [24]. PG has also been reported to occur with other molecularly targeted agents including sunitinib, imatinib [25], adalumimab and infliximab [26]. Auto-inflammatory syndromes refer to a group of inflammatory diseases not caused by infectious, allergic, autoimmune or immunodeficiency syndromes [27]. Two of
Curr Infect Dis Rep (2015) 17:23
these, pyogenic arthritis-pyoderma gangrenosum-acne (PAPA) syndrome and deficiency of IL-1 receptor antagonist (DIRA) syndrome, feature PG as a common skin manifestation. Both diseases result from genetic mutations generating increased interleukin 1 activation [27]. High values of other proinflammatory cytokines, chemokines and tissue damage effector molecules have been discovered in lesional skin of PG, including interleukins 8 and 23 [28, 29]. Despite these new insights into PG, the exact pathogenesis remains unexplained. The rarity of PG in the setting of B cell lymphoma (only one possible case in the literature in the last 20 years not related to rituximab) suggests that this collection of 6 cases is unlikely to be caused by B cell lymphoma alone and appears more likely to relate to introduction of rituximab therapy. This is further supported by the known action of rituximab on neutrophils, and the occurrence of PG with other molecularly targeted agents acting on the immune system.
Conclusion We describe six cases of vulvovaginal pyoderma gangrenosum presenting as deep suppurative ulceration associated with rituximab use in patients with B cell non Hodgkin’s lymphoma. The ulcers presented in a site rarely reported with PG and lesions were large and deep with vaginal extension. There was no spontaneous improvement and two cases developed tracks or fistulas to the anus. All cases responded dramatically to highdose IVIG or immunosuppressive treatment and cessation of rituximab. The known action of rituximab on neutrophils is a mechanism consistent with development of PG in our patients. Clinicians need to be aware of this distressing vulvar complication in female patients following treatment with this drug. Severe non infective vulvovaginal ulceration occurring in the setting of therapy for B cell lymphoma should be an indication to cease rituximab therapy and commence immunosuppressive therapy or IVIG. Compliance with Ethics Guidelines Conflict of Interest Gayle Fischer, Jack Sobel, Craig James, Ian Hamann and Priya Selva-Nayagam have no relevant disclosures. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by the author.
References 1. Adler MJ, Dimitrov DS. Therapeutic antibodies against cancer. Hematol Oncol Clin North Am. 2012;26(3):447–81. 3.
Page 5 of 6 23 2. Satoh M, Yamamoto T. Genital pyoderma gangrenosum: report of two cases and published work review of Japanese cases. J Dermatol. 2013;40(10):840–3. 3. Hadi A, Lebwohl M. Clinical features of pyoderma gangrenosum and current diagnostic trends. J Am Acad Dermatol. 2011;64(5):950–4. 4. Dixit S, Selva-Nayagam P, Hamann I, Fischer G. Vulvovaginal pyoderma gangrenosum secondary to rituximab therapy. J Low Genit Tract Dis 2014. 5. Walsh M, Leonard N, Bell H. Superficial granulomatous pyoderma of the vulva in a patient receiving maintenance rituximab (mabthera) for lymphoma. J Low Genit Tract Dis. 2011;15(2):158–60. 6. Casulo C, Maragulia J, Zelenetz AD. Incidence of hypogammaglobulinemia in patients receiving rituximab and the use of intravenous immunoglobulin for recurrent infections. Clin Lymphoma Myeloma Leuk. 2013;13(2):106–11. 7. Tsuboi H. Case of pyoderma gangrenosum showing oral and genital ulcers, misdiagnosed as Behcet’s disease at first medical examination. J Dermatol. 2008;35(5):289–92. 8. Reed BG, Shippey S, Kremp A, Belin E. Vulvar pyoderma gangrenosum originating from a healed obstetric laceration. Obstet Gynecol. 2013;122(2 Pt 2):452–5. 9. Roé E, Dalmau J, García-Navarro X, Corella F, Monfort D, Busquets D, et al. A case of vulvar pyoderma gangrenosum associated with collagenous colitis. Dermatology. 2006;213(3):234–5. 10. Valmadre S, Gee A, Dalrymple C. Pyoderma gangrenosum of the vulva. Aust N Z J Obstet Gynaecol. 2002;42(5):548–9. 11. Sau M, Hill NC. Pyoderma gangrenosum of the vulva. BJOG. 2001;108(11):1197–8. 12. Borum ML, Cannava M, Myrie-Williams C. Refractory, disfiguring vulvar pyoderma gangrenosum and Crohn’s disease. Dig Dis Sci. 1998;43(4):720–2. 13. Garcovich S, Gatto A, Ferrara P, Garcovich A. Vulvar pyoderma gangrenosum in a child. Pediatr Dermatol. 2009;26(5):629–31. 14. Langeland T, Rokkones E. Pyoderma gangrenosum as a cause of spontaneous vulvovaginal ulceration. Acta Obstet Gynecol Scand. 2004;83(12):1220–1. 15. Ahronowitz I, Harp J, Shinkai K. Etiology and management of pyoderma gangrenosum: a comprehensive review. Am J Clin Dermatol. 2012;13(3):191–211. 16. Su WP, Davis MD, Weenig RH, Powell FC, Perry HO. Pyoderma gangrenosum: clinicopathologic correlation and proposed diagnostic criteria. Int J Dermatol. 2004;43(11):790–800. 17. Lehman JS, Bruce AJ, Wetter DA, Ferguson SB, Rogers RS. Reactive nonsexually related acute genital ulcers: review of cases evaluated at mayo clinic. J Am Acad Dermatol. 2010;63(1):44–51. 18. Dixit S, Bradford J, Fischer G. Management of nonsexually acquired genital ulceration using oral and topical corticosteroids followed by doxycycline prophylaxis. J Am Acad Dermatol. 2013;68(5):797–802. 19. Curtis C, Douglas I. Pyoderma gangrenosum in a syringe driver site of a patient with non-Hodgkin’s lymphoma. Palliat Med. 2006;20(2): 113–4. 20. Pereira N, Brites MM, Gonçalo M, Tellechea O, Figueiredo A. Pyoderma gangrenosum—a review of 24 cases observed over 10 years. Int J Dermatol. 2013;52(8):938–45. 21. Miall FM, Harman K, Kennedy B, Dyer MJ. Pyoderma gangrenosum complicating pegylated granulocyte colony-stimulating factor in Hodgkin’s lymphoma. Br J Haematol. 2006;132(1):115–6. 22. Tesfa D, Gelius T, Sander B, Kimby E, Fadeel B, Palmblad J, et al. Late-onset neutropenia associated with rituximab therapy: evidence for a maturation arrest at the (pro) myelocyte stage of granulopoiesis. Med Oncol. 2008;25(4):374–9. 23. Cartron G, Watier H, Golay J, Solal-Celigny P. From the bench to the bedside: ways to improve rituximab efficacy. Blood. 2004;104(9): 2635–42.
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Page 6 of 6
24. Nakagawa T, Natsume A, Satoh M, Niwa R. Nonfucosylated antiCD20 antibody potentially induces apoptosis in lymphoma cells through enhanced interaction with FcgammaRIIIb on neutrophils. Leuk Res. 2010;34(5):666–71. 25. Pinato DJ, Sharma R. Imatinib induced pyoderma gangrenosum. J Postgrad Med. 2013;59(3):244. 26. Brunasso AM, Laimer M, Massone C. Paradoxical reactions to targeted biological treatments: a way to treat and trigger? Acta Derm Venereol. 2010;90(2):183–5. 27. Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9(3):232–46.
Curr Infect Dis Rep (2015) 17:23 28. Marzano AV, Fanoni D, Antiga E, Quaglino P, Caproni M, Crosti C, 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;178:48–56. 29. Guenova E, Teske A, Fehrenbacher B, Hoerber S, Adamczyk A, Schaller M, et al. Interleukin 23 expression in pyoderma gangrenosum and targeted therapy with ustekinumab. Arch Dermatol. 2011;147(10):1203–5.
GENITOURINARY INFECTIONS (J SOBEL, SECTION EDITOR)
Rituximab Causing Deep Ulcerative Suppurative Vaginitis/Pyoderma Gangrenosum Priya Selva-Nayagam & Gayle Fischer & Ian Hamann & Jack Sobel & Craig James
# Springer Science+Business Media New York 2015
Abstract Pyoderma gangrenosum (PG) is a rare cause of purulent vulvovaginal ulceration. Six recent cases of vulvovaginal pyoderma gangrenosum associated with rituximab are described. All cases were seen in the setting of rituximab used for the treatment of B cell non Hodgkin’s lymphoma (NHL). Age range was 50–74; symptoms were present for 2–24 months and severe pain, heavy discharge and large, deep purulent ulcers extending into the vagina were seen. This ar-
ticle reviews previous reports of vulvovaginal pyoderma gangrenosum, discusses important differential diagnoses in this setting, and provides evidence supporting rituximab as the cause of pyoderma gangrenosum in this cohort. Keywords Vulvovaginal pyoderma gangrenosum . Rituximab . Vulvovaginal ulceration . Intravenous immunoglobulin . Non Hodgkin’s lymphoma . Neutrophilic dermatosis . Pyoderma gangrenosum . Rituximab complications . Vulvovaginal discharge
This article is part of the Topical Collection on Genitourinary Infections P. Selva-Nayagam (*) Department of Dermatology, Queen Elizabeth Hospital, Adelaide, Australia e-mail: [email protected] P. Selva-Nayagam Department of Gynecology, Royal Adelaide Hospital, Adelaide, Australia G. Fischer Department of Dermatology, Royal North Shore Hospital, Sydney, Australia G. Fischer The University of Sydney, Sydney, Australia I. Hamann Mid North Coast Dermatology, Port Macquarie, Australia I. Hamann The Department of Dermatology, Westmead Hospital, Sydney, Australia J. Sobel Department of Internal Medicine, School of Medicine, Wayne State University, Detroit, MI, USA C. James Adelaide Pathology Partners, Adelaide, Australia
Introduction Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody. It is directed against the CD20 antigen, found on the surface of normal and malignant B lymphocytes. It was the first monoclonal antibody developed as a specific cancer agent, and was approved in 1997 for the treatment of low-grade B cell non Hodgkin lymphoma (NHL) [1]. Since that time, its therapeutic use has expanded significantly to other B cell malignancies and a large number of autoimmune diseases. In 2010, its sales were estimated to be in excess of $US6.8 billion worldwide [1]. Deep, purulent, vulvovaginal ulceration suggests consideration of an infective or inflammatory process. The latter includes non sexually acquired acute genital ulceration (NSAG U), Behcet’s syndrome, Crohn’s disease and pyoderma gangrenosum (PG). PG is an inflammatory, ulcerative, chronic dermatosis of unknown aetiology [2]. The diagnosis is based on clinical features, exclusion of other infective/non infective causes of ulceration and presence of associated diseases [3]. We recently published a series of four women who developed deep,
23
Curr Infect Dis Rep (2015) 17:23
Page 2 of 6
purulent vulvovaginal ulceration in the setting of rituximab therapy for B cell NHL [4]. One previous case has been documented in the literature [5], and we have seen a further sixth case recently. We describe the clinical features of these cases and highlight the association with rituximab.
Materials, Methods and Results The case notes of our five cases were reviewed and a literature search was undertaken using the criteria ‘Rituximab and vulvovaginal Pyoderma Gangrenosum’. The clinical features, investigations and treatment of five of ours, and the one previous case report in the literature are summarised in Table 1. A literature search was also conducted for vulvovaginal PG and genital PG in the last 20 years, and the nine other reported cases with vulvovaginal PG are summarised in Table 2. All six Rituximab related patients were treated with this for B cell NHL, three had additional cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone (CHOP) and two cyclophosphamide, vincristine and prednisone (CVP). The age range of women was 50–74 years; average 59 years. All patients complained of severe pain, and four of six also had heavy discharge. Duration of symptoms ranged from 1.5 to 24 months, average 10 months. Large, deep purulent vulvar ulcers were observed in all patients and five of six patients also suffered extensive involvement of the vagina (Fig. 1). All patients with a heavy discharge had significant vaginal involvement and a longer duration of symptoms (average Table 1
11 months compared to 1.5). There was no history of fever typically associated with NSAGU prodrome. Two patients (case 1 and 3) had abdominal and perianal symptoms with anal inflammation, mucous discharge and perianal ulcer. Both patients underwent endoscopy and colonoscopy with negative findings whilst one (case 1) had anoscopy and biopsy confirming involvement of the anal canal with PG. Two patients (case 1 and 2) had crater-like holes suggesting an underlying fistulous tract (Fig. 1). MRI in these patients revealed a tract in one heading from the vulva towards the anus, and a fistula in another extending to the anus. Two patients (case 1 and 2) had urinary symptoms of severe frequency and urgency. Cystoscopy revealed chronic cystitis in one (case 1) and was normal in the other (case 2). The chronic cystitis case was associated with CMV and BK virus infection, and improved following treatment with intravesical ganciclovir. Her immunosuppression was ceased and treatment changed to intravenous immunoglobulin (IVIG). The bladder symptoms of case 2 improved and cleared with treatment of the PG. All patients had repeated negative vulvar cultures and histopathology consistent with PG. Two patients (case 1 and 3) developed hypogammaglobulineamia, a well-described side effect of rituximab [6]. All six cases responded to immunosuppression or IVIG therapy plus withdrawal of rituximab, with complete healing of ulcers. Azathioprine and prednisolone were used in case 1 and 3. Both cases were changed to IVIG 2 g/kg monthly infusions
Presentation, clinical features and treatment of six cases with PG associated with rituximab
Pt. no/age
Initial diagnosis
Treatment
Vulvovaginal symptoms
Treatment for PG
1/62
NHL
R-CHOP
Prednisolone, azathioprine, good response, changed to IVIG with diagnosis of CMV and BKvirus cystitis
2/50
NHL
3/56
NHL
R-CHOP followed by 3-monthly rituximab 3-monthly rituximab
4/60
NHL
3-monthly rituximab
8 months of pain, discharge, deep vulvar ulceration, perianal mucous discharge, irritation and diarrhoea. Severe urinary frequency and urgency 14 months itch, discharge, discomfort, pain. Urinary frequency and urgency 5 months of heavy discharge, followed by painful ulceration. Intermittent diarrhoea. Jan 2011—dysuria, vaginal burning, heavy discharge
5/74
NHL, autoimmune haemolytic anaemia NHL
Rituximab and IVIG infusions 2–3 monthly
2 years severe purulent discharge, deep vulvar ulcers
CHOP 2003, relapse in 2007, R-CVP Ongoing 3 monthly rituximab infusions
6 weeks pain, bleeding, rapidly progressing ulceration
6/51 [5]
Prednisolone, IVIG
Prednisolone and azathioprine, no response, changed to IVIG Varying doses of prednisolone, which patient did not tolerate (insomnia). High-dose methotrexate (30 mg/week) led to resolution 10 % hydrocortisone cream, intra-vaginal and on vulva daily. Ongoing daily intravaginal hydrocortisone cream as maintenance Prednisolone and minocycline
Curr Infect Dis Rep (2015) 17:23
Page 3 of 6 23
Table 2
Nine reported cases of vulvovaginal PG unrelated to rituximab
Case no/age citation
Presentation
OE
Associated conditions
Treatment
1/74 [3] 2/47 [7] 3/29 [8] 4/44 [9] 5/19 [10] 6/73 [11] 7/44 [12] 8/10 [13] 9/55 [14]
Painful vulvar ulcer 2 years
Nil
Rapid onset painful vulvar and vaginal ulcer Breakdown of obstetric laceration, painful and expanding over 6 weeks Large vulvar ulcer
Deep large vulvar ulcer covered in yellow material Large vaginal and perineal ulcer with yellow slough Large deep ulcer involving labia on R side extending to clitoris Large ulcer involving r side vulva
Prednisolone 20 mg/day Colchicine, changed to prednisolone 15 mg/day Cyclosporine
Collagenous colitis
2 months of pain
2.5-cm ulcer R lower labia majora
Nil
Cyclosporine + topical tacrolimus Prednisolone 30 mg/day
6 weeks of vulvar pain
Large and multiple ulcers with adherent slough Large deep sloughy ulcers
MDS
Prednisolone 50 mg/day
Crohn’s disease
Cyclosporine
L labial ulcer with raised tender, undermined border Deep ulceration of the vulva, vagina and the R gluteal region
Nil
Cyclosporine 3.5 mg/kg and prednisolone 10 mg/day Cyclosporine 5 mg/kg/day
Rapid onset of painful ulceration Painful pustule, which rapidly evolved into an ulcer Rapidly progressing painful redness and infiltration of the skin, followed by necrotisation
once CMV and BK virus was discovered in case 1 and due to poor response in case 3. Case 2 was treated with prednisolone for rapid response followed by high-dose IVIG monthly. Case 4 responded to high-dose (30 mg weekly) oral methotrexate, case 5 cleared with topical and intra-vaginal hydrocortisone 10 % cream and case 6 prednisolone and minocycline. IVIG was considered ideal treatment given the hypo-gammaglobulineamia in two patients and increased risk of lymphoma recurrence with immunosuppression. Case 1–5 cleared completely of their ulcers and discharge. Case 1 and 4 have remained free of their disease on no treatment with 6 months follow-up. Case 2 and 3 had a recurrence of their vaginal discharge, bladder and bowel symptoms, respectively, 7 and 9 months after IVIG was ceased and have required further IVIG infusions with good
Myelodysplastic syndrome (MDS). Nil
Nil
response. Case 5 has required ongoing intra-vaginal hydrocortisone daily for control of the discharge. Repeat challenge with rituximab has not been necessary. No further information is available on case 6. Nine other cases of vulvovaginal PG have been reported in the literature in the last 20 years (Table 2) [3, 7–14]. The age range was 10–68 years; average 43 years. The duration of symptoms was shorter compared to our series, with all but two claiming symptoms for less than 30 days. This series included a solitary child aged 10 years (case 8). This patient had preceding fever and lymphadenopathy, no associated systemic disease and apparent short-duration vulvar ulceration. This raises the possibility of NSAGU. All reported patients underwent immunosuppression treatment with clearance of ulcers; four of nine had underlying systemic disease (myelodysplastic syndrome 2 and inflammatory bowel disease 2).
Discussion
Fig 1 Extensive deep purulent ulceration extending into the vagina with a heavy discharge. Arrow, crater-like hole
Pyoderma gangrenosum is a rare, deep ulcerating, neutrophilic dermatosis [15]. The presentation of a patient with painful purulent vulvar ulcers generates a large list of potential differential diagnoses. Infections, malignancy, vascular disease, drugs, vasculitis, exogenous injury, Behcet’s disease, NSAGU and other neutrophilic dermatoses need to be excluded before designation as pyoderma gangrenosum [3]. Helpful clinical features for PG include site (usually lower limbs), pathergy, associated systemic disease, follicular-based pustules as the
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initial lesion, heavy purulent discharge, undermined violaceous border and crater-like holes with cribriform scarring in healed lesions. Crater-like holes refer to openings of fistulous tracts from which pus can be expressed on applying pressure. This is regarded as an important sign for PG. The histopathology of PG is non specific, and biopsy is predominantly employed to exclude other differential diagnoses [3]. Despite these difficulties, diagnostic criteria for PG have been proposed. Diagnosis requires both major criteria and at least two minor criteria. Major criteria: 1. Rapid progression of a painful, necrolytic, cutaneous ulcer with an irregular, violaceous and undermined border. 2. Other causes of cutaneous ulceration have been excluded. Minor criteria: 1. History suggestive of pathergy, or clinical finding of cribriform scarring. 2. Systemic diseases associated with PG. 3. Histopathologic findings (sterile dermal neutrophilia, ± mixed inflammation, ± lymphocytic vasculitis), 4. Rapid response’ to immunosuppressive treatment [16]. All six cases of vulvar PG in the setting of rituximab and B cell NHL developed large painful ulcers over months to years with ragged irregular borders. A profuse heavy discharge was seen in four of six patients, histology was consistent with PG and cultures were negative. A rapid response to immunosuppression/ IVIG therapy was characteristic of all our cases. Non sexually acquired acute genital ulceration (NSAGU) is similar in its non infective findings and non specific histology. The clinical features, however, are significantly different. NSAGU ulcers are well demarcated and although occasionally can be large and painful, appear self limiting [17, 18]. They affect young adolescent girls with no underlying systemic disease. In contrast, our youngest patient was 50. All had large poorly demarcated and persistent ulcers, lasting months to years with no tendency to spontaneous healing. Two of our patients also had crater-like holes (case 1 and 2) with fistulous tracts (Fig. 2). PG lesions in adults most commonly affect the lower limbs [15], and involvement of vulvar skin is rare. Apart from the described six cases, only nine previous cases have been reported in the literature over the past 20 years. Of these, 44 % (four of nine) had associated underlying disease, which is similar to other reported series of PG. Two cases had myelodysplastic
Fig 2 a Case 5 presentation, showing inflammation oedema, heavy purulent discharge and deep ulceration. b Case 5 healed following treatment, showing clearance but with scarring typically seen in PG
Curr Infect Dis Rep (2015) 17:23
syndrome, but there were no cases with NHL or use of rituximab. By contrast, all six cases described in this paper had an association with B cell systemic non Hodgkin’s lymphoma. Underlying haematologic malignancy is an uncommon but well-described association with PG. A recent comprehensive review of all published series of PG suggested an incidence of approximately 5 % [15]. Of the 35 patients with haematologic malignancy, leukaemia was the most commonly reported in 13 patients, whilst B cell non Hodgkin’s lymphoma has been reported in only 1 case. The treatment regime in this lymphomaassociated case was not disclosed. A PubMed search of the last 20 years using the terms ‘Non Hodgkin Lymphoma and PG’ revealed a solitary case report with B cell lymphoma [19]. This patient was also treated with rituximab (and CHOP) prior to his PG developing as a pathergic lesion at a syringe driver site on his arm. PG is an inflammatory skin condition included in the spectrum of neutrophilic and auto-inflammatory syndromes [20]. Although the neutrophils seen on histopathology of PG appear morphologically normal, a number of studies have demonstrated functional abnormality of these cells [15]. [21] The importance of neutrophils in PG is also illustrated by the precipitation of the disease by granulocyte colony stimulating factor (GCSF) [21]. Rituximab acts on neutrophils in several ways. Late onset neutropenia (LON) occurring post 4 weeks after rituximab therapy appears in 5–27 % of lymphoma patients. This is thought to be a result of maturation arrest at the promyelocyte stage in the bone marrow [22]. Rituximab induces apoptosis, antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) [23]. Both complement activation and antibody binding via FCγ receptor results in direct activation of neutrophils [23]. A recent study has suggested that neutrophils are also important in direct apoptosis of lymphoma cells by rituximab via cross-linking of the FcRIIIb receptor on these cells [24]. PG has also been reported to occur with other molecularly targeted agents including sunitinib, imatinib [25], adalumimab and infliximab [26]. Auto-inflammatory syndromes refer to a group of inflammatory diseases not caused by infectious, allergic, autoimmune or immunodeficiency syndromes [27]. Two of
Curr Infect Dis Rep (2015) 17:23
these, pyogenic arthritis-pyoderma gangrenosum-acne (PAPA) syndrome and deficiency of IL-1 receptor antagonist (DIRA) syndrome, feature PG as a common skin manifestation. Both diseases result from genetic mutations generating increased interleukin 1 activation [27]. High values of other proinflammatory cytokines, chemokines and tissue damage effector molecules have been discovered in lesional skin of PG, including interleukins 8 and 23 [28, 29]. Despite these new insights into PG, the exact pathogenesis remains unexplained. The rarity of PG in the setting of B cell lymphoma (only one possible case in the literature in the last 20 years not related to rituximab) suggests that this collection of 6 cases is unlikely to be caused by B cell lymphoma alone and appears more likely to relate to introduction of rituximab therapy. This is further supported by the known action of rituximab on neutrophils, and the occurrence of PG with other molecularly targeted agents acting on the immune system.
Conclusion We describe six cases of vulvovaginal pyoderma gangrenosum presenting as deep suppurative ulceration associated with rituximab use in patients with B cell non Hodgkin’s lymphoma. The ulcers presented in a site rarely reported with PG and lesions were large and deep with vaginal extension. There was no spontaneous improvement and two cases developed tracks or fistulas to the anus. All cases responded dramatically to highdose IVIG or immunosuppressive treatment and cessation of rituximab. The known action of rituximab on neutrophils is a mechanism consistent with development of PG in our patients. Clinicians need to be aware of this distressing vulvar complication in female patients following treatment with this drug. Severe non infective vulvovaginal ulceration occurring in the setting of therapy for B cell lymphoma should be an indication to cease rituximab therapy and commence immunosuppressive therapy or IVIG. Compliance with Ethics Guidelines Conflict of Interest Gayle Fischer, Jack Sobel, Craig James, Ian Hamann and Priya Selva-Nayagam have no relevant disclosures. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by the author.
References 1. Adler MJ, Dimitrov DS. Therapeutic antibodies against cancer. Hematol Oncol Clin North Am. 2012;26(3):447–81. 3.
Page 5 of 6 23 2. Satoh M, Yamamoto T. Genital pyoderma gangrenosum: report of two cases and published work review of Japanese cases. J Dermatol. 2013;40(10):840–3. 3. Hadi A, Lebwohl M. Clinical features of pyoderma gangrenosum and current diagnostic trends. J Am Acad Dermatol. 2011;64(5):950–4. 4. Dixit S, Selva-Nayagam P, Hamann I, Fischer G. Vulvovaginal pyoderma gangrenosum secondary to rituximab therapy. J Low Genit Tract Dis 2014. 5. Walsh M, Leonard N, Bell H. Superficial granulomatous pyoderma of the vulva in a patient receiving maintenance rituximab (mabthera) for lymphoma. J Low Genit Tract Dis. 2011;15(2):158–60. 6. Casulo C, Maragulia J, Zelenetz AD. Incidence of hypogammaglobulinemia in patients receiving rituximab and the use of intravenous immunoglobulin for recurrent infections. Clin Lymphoma Myeloma Leuk. 2013;13(2):106–11. 7. Tsuboi H. Case of pyoderma gangrenosum showing oral and genital ulcers, misdiagnosed as Behcet’s disease at first medical examination. J Dermatol. 2008;35(5):289–92. 8. Reed BG, Shippey S, Kremp A, Belin E. Vulvar pyoderma gangrenosum originating from a healed obstetric laceration. Obstet Gynecol. 2013;122(2 Pt 2):452–5. 9. Roé E, Dalmau J, García-Navarro X, Corella F, Monfort D, Busquets D, et al. A case of vulvar pyoderma gangrenosum associated with collagenous colitis. Dermatology. 2006;213(3):234–5. 10. Valmadre S, Gee A, Dalrymple C. Pyoderma gangrenosum of the vulva. Aust N Z J Obstet Gynaecol. 2002;42(5):548–9. 11. Sau M, Hill NC. Pyoderma gangrenosum of the vulva. BJOG. 2001;108(11):1197–8. 12. Borum ML, Cannava M, Myrie-Williams C. Refractory, disfiguring vulvar pyoderma gangrenosum and Crohn’s disease. Dig Dis Sci. 1998;43(4):720–2. 13. Garcovich S, Gatto A, Ferrara P, Garcovich A. Vulvar pyoderma gangrenosum in a child. Pediatr Dermatol. 2009;26(5):629–31. 14. Langeland T, Rokkones E. Pyoderma gangrenosum as a cause of spontaneous vulvovaginal ulceration. Acta Obstet Gynecol Scand. 2004;83(12):1220–1. 15. Ahronowitz I, Harp J, Shinkai K. Etiology and management of pyoderma gangrenosum: a comprehensive review. Am J Clin Dermatol. 2012;13(3):191–211. 16. Su WP, Davis MD, Weenig RH, Powell FC, Perry HO. Pyoderma gangrenosum: clinicopathologic correlation and proposed diagnostic criteria. Int J Dermatol. 2004;43(11):790–800. 17. Lehman JS, Bruce AJ, Wetter DA, Ferguson SB, Rogers RS. Reactive nonsexually related acute genital ulcers: review of cases evaluated at mayo clinic. J Am Acad Dermatol. 2010;63(1):44–51. 18. Dixit S, Bradford J, Fischer G. Management of nonsexually acquired genital ulceration using oral and topical corticosteroids followed by doxycycline prophylaxis. J Am Acad Dermatol. 2013;68(5):797–802. 19. Curtis C, Douglas I. Pyoderma gangrenosum in a syringe driver site of a patient with non-Hodgkin’s lymphoma. Palliat Med. 2006;20(2): 113–4. 20. Pereira N, Brites MM, Gonçalo M, Tellechea O, Figueiredo A. Pyoderma gangrenosum—a review of 24 cases observed over 10 years. Int J Dermatol. 2013;52(8):938–45. 21. Miall FM, Harman K, Kennedy B, Dyer MJ. Pyoderma gangrenosum complicating pegylated granulocyte colony-stimulating factor in Hodgkin’s lymphoma. Br J Haematol. 2006;132(1):115–6. 22. Tesfa D, Gelius T, Sander B, Kimby E, Fadeel B, Palmblad J, et al. Late-onset neutropenia associated with rituximab therapy: evidence for a maturation arrest at the (pro) myelocyte stage of granulopoiesis. Med Oncol. 2008;25(4):374–9. 23. Cartron G, Watier H, Golay J, Solal-Celigny P. From the bench to the bedside: ways to improve rituximab efficacy. Blood. 2004;104(9): 2635–42.
23
Page 6 of 6
24. Nakagawa T, Natsume A, Satoh M, Niwa R. Nonfucosylated antiCD20 antibody potentially induces apoptosis in lymphoma cells through enhanced interaction with FcgammaRIIIb on neutrophils. Leuk Res. 2010;34(5):666–71. 25. Pinato DJ, Sharma R. Imatinib induced pyoderma gangrenosum. J Postgrad Med. 2013;59(3):244. 26. Brunasso AM, Laimer M, Massone C. Paradoxical reactions to targeted biological treatments: a way to treat and trigger? Acta Derm Venereol. 2010;90(2):183–5. 27. Braun-Falco M, Ruzicka T. Skin manifestations in autoinflammatory syndromes. J Dtsch Dermatol Ges. 2011;9(3):232–46.
Curr Infect Dis Rep (2015) 17:23 28. Marzano AV, Fanoni D, Antiga E, Quaglino P, Caproni M, Crosti C, 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;178:48–56. 29. Guenova E, Teske A, Fehrenbacher B, Hoerber S, Adamczyk A, Schaller M, et al. Interleukin 23 expression in pyoderma gangrenosum and targeted therapy with ustekinumab. Arch Dermatol. 2011;147(10):1203–5.
