Varicella Zoster infections increased in MS patients.

varicella_virus-shingles1

A new study has shown that VZ virus infections are increasing in patients suffering from MS.

Multiple Sclerosis (MS): which is also known by other names such as Encephalomyelitis disseminata, or disseminated sclerosis is an immune mediated inflammatory disease. In it, the myelinated axons in the central nervous system are affected and results in the destruction of the myelin and the axon. This disruption harms the parts of nervous system which are involved in communication, and causes significant physical disabilities.Signs and symptoms range from physical to mental and sometimes psychiatric problems as well. The full cause is unknown but seems like it is the consequence of combination of genetic susceptibilities and other factors (non genetic) like viral infections or low vitamin D levels. Together these can derive a self sustaining autoimmune disorder which can lead to recurrent immune attacks on the central nervous system.

Varicella Zoster Virus (VZV): is one of the 8 herpes viruses. Other names for this virus include… Chickenpox virus, Zoster virus and Human Herpes virus type 3. After first infection (chickenpox) the virus goes dormant. The host immunological mechanism suppresses the virus’s replication but if in future this mechanism becomes weak or compromised, the virus can easily reactivate and can cause number of neurological conditions. 

The virus causes chickenpox and once infected can cause recurrent localize infection, shingles. Early symptoms of shingles include photo-phobia, headache, flu like symptoms, pain on skin, rashes, blisters which open up and scab.

Fingolimod: is a sphingosine 1 phosphate receptor modulator, a pro-drug which is converted to its active metabolite by the action of sphingosine kinase. The active form is fingolimod phosphate. It is responsible for preventing the lymphocytes exiting from the lymph nodes and thereby lowers the lymphocyte count in peripheral blood. It brings about this action by binding to the sphingosine 1 phosphate receptors 1, 3, 4 & 5. This helps in MS by reducing journey of the lymphocytes into the CNS.

Increased VZV infections in MS patients: this issue requires attention because of the two cases which resulted in the death of the patients. One incident occured in April 2013, a patient was taking fingolimod therapy followed by treatment with natalizumab and a 3 months washout period, developed a reactivated Zoster infection.

Another case took place in 2008. A participant in a clinical trial was on fingolimod  for 10 months and died due to  disseminated primary VZV infection.

Study: to find out about the risks of VZV infections in MS patients.

Aim: to discover the risk factors, clinical characteristics of VZV infections in patients who are on fingolimod and to produce new recommendations for its prevention and management.

Trials: were based on pooled data from the completed controlled phase 2 & 3 studies which included about 3,916 participants and an ongoing uncontrolled extension phases having 3,553 participants. The drugs used were fingolimod 0.5 or 1.25 mg/d, interferon beta -1a and a placebo. Both male and females ranging 18-55 years were included who were previously diagnosed with a relapsing- remitting multiple sclerosis. In Post Marketing Setting, the cases which were reported since 2012 for patients on fingolimod 0.5mg/d were assessed.

Results: in overall trials, the VZV rates weren’t high but were greater with the use of fingolimod when compared to the placebo use. Results received from the post marketing surveillances were comparable (7 per 1000 patients). Disproportionality in reporting herpes zoster infections was higher for patients on fingolimod as compared to those receiving other disease modifying treatments. It is believed that treatment with corticosteroids for relapses might pose a risk factor for VZV infections.

Conclusion: so, it was concluded by the researchers that the rates of VZV infections found in clinical trials were low with fingolimod but was higher than the recipients on placebo.

Dr. Putski, “our article, which is the result of a consensus meeting with the experts in the fields of infectious diseases and multiple sclerosis, provides general guidance on risk mitigation, this includes vigilance & appropriate HZ infection prevention & management, relevant to physicians when prescribing MS DMT”

Kenneth Tyler, Md at University of Colorado, School of Medicine said that there are other data available as well which portray a connection between VZV and fingolimod. This drug compared to other medications used in MS treatment  significantly increase the risk of VZV infections but has not shown to increase infections resulting from other pathogens or causative agents.

Dr. Jerry S. Wolinsky, Professor of Neurology at University of Texas Health Science Centre, stated that for every 1000 healthy patients, 4 are expected to develop shingles and people with MS who are not on therapy, the number is probably 6 which makes it twice as compared to normal population. 

Labeling: the current labeling of fingolimod does not specify about the zoster infection risks, but it do propose that the patients who were not vaccinated against this virus or have a missing history on chickenpox immunization should be vaccinated for VZV before starting therapy with fingolimod. The patient should start the treatment after 1 month of the immunization.

Mechanism of infection: VZv is one of the organism which is repressed by pathogen specific memory T cells and fingolimod blocks the migration of T lymphocytes out of the lymphatic system. This relation may be the cause of the increased infection risk with fingolimod.

K. Tyler proposed that another possibility could be that VZV is dependent on the fingolimod specific target site i.e. sphingosine 1 phosphate receptor for the completion of its life cycle. Though this relation is not fully proven yet.

Although the risks are low but the adverse events reports have declared that the risks are much higher than average on comparison with all other MS treatments.

Recommendations:

1. it is now recommended that the patients should be checked for their VZV immune status and immunization who are more susceptible to primary VZV infections before starting the treatment with fingolimod.

2. Individual risk – benefit assessment is now becoming a crucial part for the patients who are using concomitant pulsed corticosteroid therapy.

3. Early detection of symptoms caused by VZV can help in the initiation of antiviral treatment on time.

4. MS patients should be vaccinated with 2 doses of Varivax/ Varilrix for upto 4 weeks apart.

5. Live attenuated vaccines are not to be given in patients taking fingolimod. vaccinations may be ineffective during & upto 2 months after withdrawing the drug. Vaccination especially live attenuated type pose a greater threat of developing infections instead of preventing them.

6. Patients who have been prescribed with corticosteroids (high doses) need to be vaccinated after stopping the corticosteroids. The vaccination should be given at least after 30 days. 

7. Centre for Disease Control advisory Committee on Immunization guidelines suggest that MS therapy should be stopped for patients who are at high risks of developing disseminated VZV infections and should be treated with IV antivirals.

8.Patients should be counseled and educated about the signs & symptoms of primary and recurrent HZ infections and that they should not take long in reporting it to their physician/pharmacist.

9. Antiviral prophylaxis is not generally required but could prove beneficial in patients who are to take high doses of corticosteroids for a longer period.

Reference:

  • JAMA neurology November 2014.
  • US Pharmacist December 10 2014.
  • Healthline blogspot.
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