The popular allergy medication cetirizine (Zyrtec, Johnson & Johnson Consumer Inc), when added to standard therapy, shows the potential to reduce the rate of relapse of the neuromyelitis optica (NMO), in a small but important study.
“We were pleased to find that cetirizine was safe and well-tolerated in our population of NMO patients,” senior author, Illana Katz Sand, MD, assistant professor of neurology at the Icahn School of Medicine at Mount Sinai, New York City, said in a press statement.
“While the study’s open-label design and small sample size preclude definitive conclusions, we did detect a signal that suggested cetirizine may be of benefit.”
The pilot study of 16 patients with NMO, published this month in the journal Neurology Neuroimmunology and Neuroinflammation, showed that treatment with 10 mg/day of oral cetirizine, a second-generation antihistamine, in addition to standard therapy for 1 year was associated with an annualized relapse rate that was significantly lower than seen during standard therapy alone, before the addition of cetirizine.
Meanwhile, the add-on therapy was described as well tolerated and safe.
NMO’s severe effects stem from inflammation and demyelination, primarily in the optic nerve (optic neuritis), spinal cord (myelitis), and brainstem. The neurologic episodes are marked by poor recovery and can result in permanent disability.
Standard disease-modifying treatments, such as mycophenolate and rituximab, focus on decreasing lymphocyte activity and are effective in off-label use in improving patient outcomes with NMO; however, breakthrough disease is common.
Preclinical studies have meanwhile shown eosinophils and granulocyte infiltration to play an important role in NMO-related inflammatory destruction, and Sand and her team found in previous animal studies that cetirizine, an eosinophil stabilizer, effectively blocked NMO spectrum disorder (NMOSD)–type lesions.
To test the treatment in humans, they enrolled patients referred by treating physicians at the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai between April 2014 and February 2015, who either met the Wingerchuk 2006 diagnostic criteria for NMO or had a typical episode, and also tested positive for NMO IgG.
Patients had a disease duration of at least 6 months and were required to be stable on their current disease-modifying therapy for at least 3 months. Exclusion criteria included existing use of a daily antihistamine, severe renal or hepatic impairment, or hypersensitivity to cetirizine.
Of 24 patients who were referred, 16 (median age, 36.5 years), including 15 women, were ultimately enrolled.
The study’s primary endpoint was met, with a statistically significant difference in the annualized relapse rate in the year before (0.4 ± 0.80) and in the year after (0.1 ± 0.24) the addition of cetirizine treatment (P = .04).
In the year before enrollment, four patients had five relapses, while there was just one relapse during the study period. None of the patients changed their disease-modifying therapy from the prestudy to study period.
Importantly, the one patient with a relapse, who was also being treated with rituximab, reported poor adherence to cetirizine, missing 3 to 4 days of treatment in the week before symptom onset.
A caveat is that among nine events contributing to the prestudy annualized relapse rate, three occurred while the patient was receiving the disease-modifying therapy for less than 6 months, which is when oral therapies are considered to reach full efficacy.
Despite that, the occurrence of just a single relapse in the study year is notable, the authors said.
“Even when the 3 episodes that occurred close to the initiation of disease-modifying therapy are removed and statistical significance is lost, it remains interesting that over the course of 1 year of follow-up of a cohort that included patients with recent breakthrough disease, there was only a single relapse that was quite mild in severity, in a participant who had been poorly adherent to cetirizine,” they write.
Other disability and tolerability endpoints showed no differences. Disability, assessed according to the Expanded Disability Status Scale, was at a mean 3.9 ± 2.18 before the intervention and at 3.2 ± 2.31 at the conclusion of the study (P = .50).
And relapse severity and tolerability, including drowsiness measured by the Epworth Sleepiness Scale, were also consistently similar throughout the study (mean, 6.5 ± 5.33 at baseline and 6.9 ± 4.50 at month 12; P = .74).
Drowsiness had been a particular concern because of cetirizine’s role as an allergy medicine, but early studies of the drug showed no sedative effect. In addition, several patients reported the added benefit of improvement in their seasonal allergies.
There were no significant differences between laboratory measures of immunologic parameters at baseline and in the year after cetirizine initiation.
“Animal model work demonstrated that the development of NMOSD-type lesions could be blocked with the administration of cetirizine, so it was exciting to see if it might be safe and effective for human NMO patients,” the authors reported.
In addition to the open-label nature of the trial and small sample size, important limitations include that the requirement for disease stability for at least 3 months before study entry could have resulted in patients with lower disease activity.
Senior author Sand noted that previous studies have shown that even when optimally managed with rituximab, considered the most effective standard-of-care treatment, nearly 20% of patients with NMO experience breakthrough relapses.
“Relapses are characterized by the acute onset of focal neurologic deficits,” she told Medscape Medical News.
“Most common in NMO are optic neuritis, myelitis, which is often longitudinally extensive, and area postrema syndrome, involving intractable hiccups, nausea, and vomiting, though brainstem, diencephalic, and hemispheric syndromes are also possible.”
Sand noted that eosinophils and other granulocytes, which are known to play a role in NMO pathophysiology from pathology studies, are present in the cerebral spinal fluid of some patients with NMO.
“When eosinophils are activated and degranulate, they cause significant destruction of nearby tissue — in the case of NMO, the optic nerves, brain, and spinal cord,” she explained.
“So from a mechanistic standpoint, it is plausible that stabilizing eosinophils in the periphery to keep them out of the CNS [central nervous system] might be of benefit in NMO.”
The study should pave the way for more robust research into the role of cetirizine vs placebo in NMO treatment, Sand said.
“A natural next step would be to do a larger, randomized trial of cetirizine as an add-on to standard NMO therapy,” she said.
“We are currently considering whether this is feasible/advisable. We are also considering whether cetirizine may be of benefit if given, perhaps in a larger dose, at the onset of a relapse.”
According to Michael Levy, MD, PhD, associate professor and director of the Neuromyelitis Optica Clinic at Johns Hopkins University, Baltimore, Maryland, there are several important clinical challenges in the treatment of NMO.
“Acute treatment of relapses is limited to therapies we used in the 1980s — high-dose corticosteroids and plasma exchange — that may provide some benefit but usually leave behind residual disability,” he told Medscape Medical News.
“We need better therapies to mitigate damage from acute relapses.”
Improved therapies are also needed for long-term treatment of NMOSD, Levy noted.
“Once the damage is done in the central nervous system of patients with NMOSD, we need better treatment options to improve neurological function, such as walking, vision, and bowel/bladder function.”
While the current findings were encouraging in showing safety and tolerability, and that cetirizine doesn’t interfere with current off-label immunosuppressive medications commonly used in NMOSD, more research is needed to determine the extent of the benefits, Levy said.
“Although the trial was conducted in an unblinded manner that may predispose to biases in the interpretation of the data, everyone agrees cetirizine was well tolerated and safe to add on to other treatments in this patient population,” Levy said.
“The benefit of adding cetirizine was less clear, and more research needs to be done to confirm a potential benefit.”
The study was funded by a research grant from the Guthy Jackson Charitable Foundation and from a philanthropic grant by the Muzio family to Mount Sinai. Sand received research support from the US Department of Defense, the National Multiple Sclerosis Society, and the Guthy Jackson Charitable Foundation. Fabian served on the speaker’s bureau of Biogen. Telford reports no disclosures. Levy has disclosed no relevant financial relationships.
Neurol Neuroimmunol Neuroinflamm. Published online February 2, 2018. Abstract
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