Association Between Fingolimod and HPV-Related Complications in Women with MS

Background: Fingolimod and other immunosuppressant drugs used to treat multiple sclerosis (MS) are associated with reactivation of viruses, including Varicella zoster virus (VZV) and the John Cunningham (JC) virus. Human papillomavirus (HPV) is responsible for 90% of cervical cancers and other anogenital cancers. There is currently no data supporting the reactivation of HPV with fingolimod or the risk of developing of HPV-related cancers. 

Objectives: To describe three cases of possible HPV reactivation or increased risk of dysplasia in women taking fingolimod.

Methods: A retrospective chart review of 3 women with MS treated with fingolimod and known HPV with varying degrees of cervical or vulvar dysplasia. 

Results:

Case 1: 57 yo F with MS on fingolimod since 2011 with HPV-related cervical dysplasia. Past treatment includes multiple other DMTs. History includes HPV+ pap test in 2001 with HPV clearance until 2015 when pap test results showed cervical LSIL and high-risk HPV, followed by HSIL/CIN2 in 2016. Patient had colposcopy and LEEP and discontinued fingolimod in 2016 due to progression of dysplasia. Patient has not received the Gardasil vaccine. 

Case 2: 45 yo F with MS on fingolimod since 2013 with elective hysterectomy in 2016 due to pelvic pain and HPV-related cervical dysplasia. No other prior DMT use. History includes abnormal pap testing, HPV status unknown, at age 18 followed by normal pap tests until 2015.  Patient had colposcopy and LEEP with continued cervical dysplasia until 2016, ending in elective hysterectomy. Patient has not received the Gardasil vaccine. 

Case 3: 28 yo F with MS on fingolimod since 12/2015 with HPV-related vulvar dysplasia. No other prior DMT use. History includes HPV+ Pap test and genital warts in 2014. These lesions were persistent until 7/2015; she then had no further evidence of disease until 6/2016 when pap results showed high risk HPV and vulvar HSIL/VIN3. Patient had colposcopy, laser ablative therapy, and is still receiving treatment for VIN 3. Patient received the Gardasil vaccine after her diagnosis of genital warts but prior to her diagnosis of VIN3.

Conclusions: There is a potential relationship between the use of fingolimod in women and the reactivation of HPV, inability to clear, and the development of HPV-related cancers.

Discussion: We have described 3 cases of women treated with fingolimod for MS with HPV-related dysplasia requiring ongoing surveillance and intervention. This suggests screening for HPV vaccination history and HPV status may be important prior to initiating fingolimod. Increased surveillance for HPV positive women on fingolimod may be appropriate. We need further research to determine if stopping fingolimod in women with high-risk HPV strains, genital dysplasia, or cancer is clinically indicated.