The use of disease-modifying therapies (DMTs) in adults with multiple sclerosis (MS) increased the risk of precancerous growth in those older than 45 years of age, according to an age-related adverse events analysis of several dozen clinical trials.
In contrast, age did not affect infection rates in MS patients using DMTs.
The study, “Age-related adverse events of disease-modifying treatments for multiple sclerosis: A meta-regression,” was published in the Multiple Sclerosis Journal.
DMTs are a class of medications that impact the different aspects of the inflammatory process that underlies the development of MS.
Clinical trials have shown the effectiveness of DMTs, in both clinical and brain imaging outcomes, by reducing the number and severity of relapses and slowing disability progression.
As DMTs are designed to influence the immune system, people prescribed these therapies may be at higher risk of infection and have a reduced immune capacity to recognize and fight abnormal cell growth that could evolve into cancer (neoplasms).
Age is considered an essential factor when assigning a DMT, as aging is associated with an increasing number of co-existing conditions (comorbidities) and the gradual deterioration of the immune system (immunosenescence).
However, the effects of age on DMT-related risk of infection and neoplasms is currently unknown as “to date, no study has formally investigated this issue,” the researchers wrote.
Investigators at San Camillo-Forlanini Hospital in Italy analyzed clinical trials that assessed DMTs in people with MS to determine the impact of age and DMT use on the risk of infections and neoplasms.
Eligible trials for this analysis were randomized and controlled trials that lasted more than one year, and tested currently available DMTs in adults with any type of MS. All compared DMTs to a placebo. Age-related adverse event data regarding infections and neoplasms were collected.
DMTs were divided into three categories based on their mechanism of action: DMTs that modulate the immune system (immunomodulatory), those that block immune cells from entering the brain and spinal cord (sequestrating), or depletive agents that decrease immune cell numbers.
The search found 807 articles, of which 45 met the established eligibility criteria. Of these, 28 articles investigated immunomodulatory therapies, nine assessed sequestrating treatments, and eight publications tested depletive agents.
Altogether, the total number of enrolled patients was 32,027 with a mean age of 38, a mean follow-up of just over two years, and 22.3% had progressive disease.
Analyzed data included 64,517 patient-years — the incidence calculated by multiplying the number of persons at risk per time — of which 34,042 were in DMT treatment arms and 30,475 in control (placebo) arms.
The analysis found the rate of any infection was 17.0 per 100 patient-years in patients treated with DMTs, compared to 15.9 per 100 patient-years in control arms. This result suggested that, when assessing DMTs all together, there is no significant association with overall infections.
When analyzed separately, only depletive DMT agents were associated with higher infection rates. Adding age alone or the mechanism of action by age to the calculation did not change the results.
An analysis of herpes simplex virus infections specifically found events rates of 1.21 per 100 patient-years in DMT treated patients, and 0.50 per 100 patient-years in control subjects.
Higher infection rates with herpes simplex were seen in those taking depletive agents and, to a lesser extent, sequestrating therapies. However, age did not impact the results.
According to the team, the lack of an association between age and increased infection rate with DMTs probably resulted from the “difficulty in discriminating between opportunistic and non-opportunistic infections,” and delays in infection development.
The rate of neoplasm adverse events was 0.40 per 100 patient-years in the DMT study arms and 0.27 in control arms. Pooled data for all DMTs was not significant, but there was a strong trend toward more neoplasms in treated participants. Overall, age had no impact.
In contrast, a direct relationship between the neoplasm rate and age in patients given depletive agents was seen.
A final analysis found that the rate of neoplasms becomes relevant above the age of 45 years in study participants treated with depletive DMT agents rather than immunomodulatory or sequestrating agents.
Overall, the “study supports a detrimental effect of age on the safety profile of depletive DMTs, with an increased incidence of neoplasms especially over 45 years of age. We failed to demonstrate an age-related increased incidence of infections,” the researchers wrote.
According to the team, the “findings suggest caution when treating patients older than 45 years of age with depletive agents,” and “may help neurologists through the decision-making process for MS treatment.”
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