Inflammatory Vaginitis in Women on Long-Term Rituximab for Autoimmune Disorders
Key findings
- Physicians at Massachusetts General Hospital report for the first time that inflammatory vaginitis can be a complication of rituximab therapy; it occurred in 16 of 454 women (3.5%) being treated for autoimmune disease
- All patients with vaginitis reported vaginal discharge; other symptoms included vaginal pain, dyspareunia and vaginal or vulvar irritation
- The nine patients with return of B cells after rituximab cessation had substantial improvement or resolution of vaginal symptoms
- In a case–control analysis, women with inflammatory vaginitis were more likely than controls to report a history of urinary tract infection (50% vs. 17%; P=0.01); no other risk factor could be identified
- This summary highlights the authors' suggested workup and treatment of rituximab-associated inflammatory vaginitis
New complications of B-cell depletion with rituximab continue to be reported, including a few case reports of vulvovaginal pyoderma gangrenosum. Now, Caroline M. Mitchell, MD, director of the Vulvovaginal Disorders Program in the Department of Obstetrics & Gynecology and researcher in the Vincent Center for Reproductive Biology at Massachusetts General Hospital, and colleagues have described inflammatory vaginitis as a possible mucocutaneous vulvovaginal complication of rituximab.
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Their observations and recommendations for management are published in BMC Women's Health.
Methods
The team consulted a database of patients treated with rituximab for autoimmune disease at the Vasculitis and Glomerulonephritis Center at Mass General between November 8, 2002, and April 29, 2020. Patients were included in the analysis if they were female, 25–90 years old, and had received at least four doses of rituximab.
Of 454 eligible patients, 16 (3.5%) had developed inflammatory vaginitis, defined as the unexplained presence of bothersome vaginal symptoms. A higher proportion of women younger than 50 (8%) developed vaginitis than those who were ≥50 (2%; P=0.004). Vaginitis diagnosis occurred a median of 44 months after rituximab initiation (range, 11–119 months).
Symptoms
All patients reported vaginal discharge, which was sometimes copious. Other symptoms were vaginal pain/dyspareunia (n=12), burning (n=7) and vaginal or vulvar irritation (n=6). One patient's vaginal pain was so severe she had to be hospitalized for IV analgesics.
Outcome of Vaginitis Therapy
Rituximab was discontinued in all 16 women and 15 received the recommended therapy for desquamative inflammatory vaginitis (vaginal clindamycin or intravaginal steroids):
- B-cell return (>10 cells/mL)—nine women; symptoms completely improved in five women and mostly improved in four
- No B-cell return—seven women; symptoms improved completely in one woman, mostly in three, and partially in three
At the time the paper was written, 10 patients continued to have vaginitis symptoms; the median duration was 18 months (range, 5–61 months).
This analysis demonstrates an association between B-cell depletion and symptoms, but does not prove that the vaginitis is caused by rituximab.
Case–Control Analysis
To identify risk factors for the development of vaginitis, the researchers matched each of the 16 women with up to three women from the same database who had no documented history of vaginal complaints (based on age, underlying autoimmune disease and the number of doses of rituximab).
Women with inflammatory vaginitis were more likely than controls to report a history of urinary tract infection (50% vs. 17%; P=0.01). There was no significant difference between groups in comorbidities; white blood cell or T-cell counts; IgA, IgM or IgG levels; creatinine; neutropenia; use of cyclophosphamide; or cumulative cyclophosphamide dose.
Suggested Management
Patients taking rituximab who develop vaginitis symptoms should be referred to a gynecologist. Findings suggestive of rituximab-associated vaginitis are:
- Vaginal pH >5
- Wet mount or gram stain showing >1 white blood cell per epithelial cell per high-power microscope field
- Absence of other infectious etiology (Candida, herpes simplex virus, Trichomonas vaginalis, Neisseria gonorrhoeae, or Chlamydia trachomatis)
Potential treatment is one of the following daily for 4–6 weeks:
- Vaginal clindamycin 2% cream, 5 g
- Vaginal hydrocortisone 10% compounded cream
- Vaginal hydrocortisone compounded 100 g suppository
If symptoms persist and continue to significantly affect quality of life, a trial of rituximab discontinuation to allow B-cell return should be considered if medically feasible.
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