DISCLAIMER :This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

Overview

Rituximab, obinutuzumab, ofatumumab, and ocrelizumab are anti-clusters of differentiation 20 (CD20) antibodies used to deplete B cells (also known as B lymphocytes) in diseases characterised by overactive, dysfunctional, or malignant B cells.^1-6 These include cancers like chronic lymphocytic leukaemia (CLL) and follicular lymphoma, as well as autoimmune diseases such as relapsing forms of multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS). Anti-CD20 antibodies specifically target CD20, a cell surface antigen on B cells, and destroy B cells through several mechanisms.

In Malaysia, there are currently 7 products containing rituximab, and 1 each containing obinutuzumab, ofatumumab, and ocrelizumab, that have been registered with the Drug Control Authority (DCA).⁷

Pyoderma gangrenosum (PG) is a rare, severe chronic, inflammatory skin disease characterised by painful nodules or pustules that progress to enlarging necrotic ulcers with undermined, irregular, erythematous-violaceous borders.^8-10 PG lesions often affect the lower limbs, but any area of the body may be involved. PG has been commonly associated with underlying systemic autoimmune disorders, such as inflammatory bowel disease, rheumatoid arthritis (RA), and haematological malignancies.

Background of the Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) received notifications from local product registration holders regarding recent safety-related labelling requirements imposed by regulatory agencies in two reference countries. Triggered by an identified safety signal by the United States Food and Drug Administration (US FDA), which led to the inclusion of PG risk in the package insert for ocrelizumab, Swissmedic raised safety concerns about the potential risk of PG associated with the class of anti-CD20 antibodies.^11-12 Consequently, Swissmedic requested updates to the product information for all related products (i.e., rituximab, obinutuzumab, ofatumumab, and ocrelizumab) in Switzerland.

Two pharmacovigilance studies on the US FDA Adverse Event Reporting System (FAERS) identified 32 cases of PG reported with the use of rituximab and indicated their significant disproportionality compared with other medicines.^13-14 Of these cases, 62.5% were female with a median age of 48 years.¹⁴ Notably, a stronger association was observed between PG and rituximab for multiple sclerosis, whereas the association was lower for RA and non-Hodgkin’s lymphoma, suggesting the potential confounding by indication.

A recent review of 16 published case reports on PG following rituximab use also observed a mean age of 53.1 years (SD 18.3 years) and a marked female predominance (7:1 ratio), with all 14 female cases presenting with vulvovaginal PG.¹⁵ The mean time-to-onset of PG was 40.9 months (SD 36.9 months), with ulcerative PG being the most prevalent variant. Besides, there were 2 published case reports of vulvovaginal PG in woman treated with ocrelizumab for multiple sclerosis.^16-17

The exact pathogenesis by which anti-CD20 antibodies lead to PG is not yet well understood.^13,16-17 Mechanistically, the widely variable onset following drug initiation (ranging from months to years) may suggest an atypical cytotoxic T-cell activation and a neutrophil response to local antigenic stimulation.^15-17 This response could follow B cell depletion and apoptosis induced by anti-CD20 antibodies therapy. In addition, the mechanism of anti-CD20 antibodies-induced inflammatory vaginitis remains unclear—it is hypothesised that prolonged B-cell depletion may dysregulate the antibody response to both pathogenic and commensal microorganisms in the vagina, leading to microbial overgrowth and inflammation.¹⁸

There is no established gold standard treatment for PG, and current treatment approaches are primarily based on expert opinion, case studies, and small cohort studies.^10,14,19 Immunosuppressive and immunomodulating drugs, such as systemic corticosteroids, intravenous immunoglobulins, and cyclosporin, were used in combination treatment for PG involving rituximab and ocrelizumab.^{10,13,15-17,19} In published case reports on PG following rituximab use, rituximab was discontinued in 12 out of 16 cases (4/16 not reported), with 75% (9/12) achieving a complete response within an average of 9.7 months (SD 3.2 months).¹⁵ Additionally, 2 published case reports of PG following ocrelizumab use also reported healing after discontinuation of ocrelizumab along with long-term management of PG.^16-17

Adverse Drug Reaction Reports²⁰

To date, the NPRA has received 426 reports with 1,010 adverse events suspected to be related to products containing rituximab, obinutuzumab, ofatumumab, and ocrelizumab. No events related to PG have been reported locally thus far. However, there has been 1 report of a related event, specifically skin ulcer, following the use of rituximab.

Advice for Healthcare Professionals

• While NPRA is still reviewing this safety issue, be aware of the potential associations between the risks of rare but high-morbidity PG with the use of anti-CD20 antibodies.
• Educate patients to watch for symptoms of PG such as painful, rapidly expanding, non-healing skin ulcerations, and specifically advise female patients to monitor any vaginal discharge or discomfort. Advise all patients to seek immediate medical care if PG symptoms occur.
• Keep a high index of suspicion for PG to aid in timely diagnosis, particularly in patients with underlying systemic autoimmune disorders.
• If PG is suspected, initiate appropriate wound care, pain control and treatment for PG. Conduct a thorough drug history for all patients presenting with suspected PG to identify any potential drug culprits.
• Consult with dermatologists and/or gynecologists (for vaginal symptoms). Carefully weigh the risks and benefits of discontinuing anti-CD20 antibodies on a case-by-case basis.
• Report all suspected adverse events associated with the use of anti-CD20 antibody products to the NPRA.

References: 

1. Marshall MJE, Stopforth RJ, Cragg MS. Therapeutic Antibodies: What Have We Learnt from Targeting CD20 and Where Are We Going?Front. Immunol. 2017 8:1245. Available from: https://doi.org/10.3389/fimmu.2017.01245
2. Fettke F, Schumacher A, Costa S-D, Zenclussen AC. B Cells: The Old New Players in Reproductive Immunology. Front Immunol. 2014, 5:285. Available from: https://doi.org/10.3389/fimmu.2014.00285
3. National Pharmaceutical Regulatory Agency (NPRA). MabThera® (rituximab) [Package Insert]. QUEST3+ Product Search. 2023 Sep [cited 2024 Feb 15]. Available from: http://www.npra.gov.my
4. National Pharmaceutical Regulatory Agency (NPRA). GAZYVATM (obinutuzumab) [Package Insert]. QUEST3+ Product Search. 2022 Jul [cited 2024 Feb 15]. Available from: http://www.npra.gov.my
5. National Pharmaceutical Regulatory Agency (NPRA). BONSPRI (ofatumumab) [Package Insert]. QUEST3+ Product Search. 2022 Jun [cited 2024 Feb 15]. Available from: http://www.npra.gov.my
6. National Pharmaceutical Regulatory Agency (NPRA). OCREVUS 300 MG/10 ML (ocrelizumab) [Package Insert]. QUEST3+ Product Search. 2023 Aug [cited 2024 Feb 15]. Available from: http://www.npra.gov.my
7. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2024 [cited 2024 Feb 20]. Available from: https://www.npra.gov.my
8. Ruocco E, Sangiuliano S, Gravina AG, Miranda A, Nicoletti G. Pyoderma gangrenosum: an updated review. Journal of the European Academy of Dermatology and Venereology. 2009, 23, 1008 –1017. Available from: DOI: 10.1111/j.1468-3083.2009.03199.x
9. Ahronowitz I, Harp J, Shinkai K. Etiology and Management of Pyoderma Gangrenosum. Am J Clin Dermatol. 2012 13 (3): 191-211. Available from: https://doi.org/10.2165/11595240-000000000-00000
10. Maronese CA, Pimentel MA, Li MM, Genovese G, Ortega-Loayza AG, Marzano AV. Pyoderma Gangrenosum: An Updated Literature Review on Established and Emerging Pharmacological Treatments. Am J Clin Dermatol. 2022 Sep;23(5):615-634. Available from: https://doi.org/10.1007/s40257-022-00699-8
11. United States Food and Drug Administration (FDA). July - September 2022 | Potential Signals of Serious Risks/New Safety Information Identified by the FDA Adverse Event Reporting System (FAERS) [Internet]. 2022 [cited 2024 Feb 15].Available from: https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/july-september-2022-potential-signals-serious-risksnew-safety-information-identified-fda-adverse
12. United States Food and Drug Administration (FDA). Drug Safety-related Labeling Changes (SrLC): ocrelizumab [Internet] 2022 Aug 18 [cited 2024 Apr 15]. Available from: https://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges/
13. Aggarwal P. Pyoderma gangrenosum adverse event with Rituximab use: A postmarketing pharmacovigilance analysis. Dermatol Ther. 2020 Mar;33(2):e13221. Available from: https://doi.org/10.1111/dth.13221
14. Hillen JB, Stanford T, Ward M, Roughead EE, Kalisch Ellett L, Pratt N. Rituximab and Pyoderma Gangrenosum: An Investigation of Disproportionality Using a Systems Biology-Informed Approach in the FAERS Database. Drugs Real World Outcomes. 2022 Dec;9(4):639-647. Available from: https://doi.org/10.1007%2Fs40801-022-00322-6
15. Croitoru D, Nathanielsz N, Seigel K, Elsawi R, Sibbald C, Alavi A, Zipursky J, Piguet V. Clinical manifestations and treatment outcomes of pyoderma gangrenosum following rituximab exposure: A systematic review. J Am Acad Dermatol. 2022 Sep;87(3):655-656. Available from: https://doi.org/10.1016/j.jaad.2021.12.028
16. Breneman AN, Eber AE. Vulvovaginal Pyoderma Gangrenosum in a Patient Treated With Ocrelizumab for Multiple Sclerosis. Journal of Lower Genital Tract Disease. 2022 Apr 26(2):p 189-191. Available from: https://doi.org/10.1097/LGT.0000000000000661
17. Klumpp A, Luessi F, Engel S, Weidenthaler-Barth B, Becker D, Grabbe S, Schepler H. Ocrelizumab-induced vulvovaginal pyoderma gangrenosum in a patient with relapsing-remitting multiple sclerosis. JAAD Case Rep. 2022 Aug 10;28:24-27. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9463556/
18. Yockey L, Dowst S, Zonozi R, Huizenga N, Murphy P, Laliberte K, Rosenthal J, Niles JL, Mitchell CM. Inflammatory vaginitis in women on long-term rituximab treatment for autoimmune disorders. BMC Womens Health. 2021 Aug 5;21(1):285. Available from: https://doi.org/10.1186%2Fs12905-021-01423-0
19. Dissemond J, Marzano AV, Hampton PJ, Ortega-Loayza AG. Pyoderma Gangrenosum: Treatment Options. Drugs. 2023 Sep;83(14):1255-1267. Available from: https://pubmed.ncbi.nlm.nih.gov/37610614/
20. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2024 [cited 2024 Feb 15]. Available from: https://www.npra.gov.my (access restricted)

Written by: Nafiza Mohd. Ismail

Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Norleen Mohamed Ali