Multiple Sclerosis Watch

Specialty Pharmacy Times, February 2011, Volume 2, Issue 1

Sildenafil Shows Promise in MS Mouse Model

Could phosphodiesterases be a new therapeutic target in MS? Researchers from Barcelona, Spain, have recently published their results from a mouse study in the January 2011 issue of Acta Neuropathologica that demonstrate a neuroprotective effect of sildenafil, the popular phosphodiesterase inhibitor used in erectile dysfunction in humans.

The scientists immunized mice to induce experimental autoimmune encephalomyelitis, an animal model of MS in humans. They injected sildenafil subcutaneously daily for 3 to 8 days; the spinal cords were removed and examined for disease progression. The researchers found that during 5 to 8 days of treatment, the clinical score for disease progression stabilized around the lower end of the scale, and more than half of the animals presented virtually full recovery, an effect that seemed to be dose dependent.

The study team theorized that as in animal models for other neurodegenerative diseases such as Alzheimer’s disease, stroke, and focal brain lesions, nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) play a significant role in MS. The complex NO-cGMP pathway is thought to activate antiapoptotic mechanisms and provide neuroprotection after cortical injury, typically seen in MS. This pathway can be terminated by phosphodiesterases, so phosphodiesterase inhibitors, such as sildenafil, may be beneficial in enhancing remyelination and preventing axonal loss in MS.

The researchers observed that sildenafil also increased the proportion of regulatory T cells in the spinal cords of the mice, cells that are important in suppressing autoreactive T cells in autoimmune diseases. Although phosphodiesterase inhibitors such as sildenafil and tadalafil have been used in the MS population to treat erectile dysfunction, the authors note “There have not been any published studies to determine if these treatments modify MS pathology.”

Pediatric-Onset MS: More Research Still Needed

Little is known about the frequency and proper management of pediatric-onset MS refractory to first-line diseasemodifying therapies (DMTs), and many studies have been conducted to attempt to elucidate guidelines for treatment. Results of a multicenter, retrospective, longitudinal study conducted by researchers for the National Network of Pediatric MS Centers of Excellence give some insight into how to manage refractory pediatric-onset MS.

The open-label study, published in the December 13, 2010, online issue of the Archives of Neurology, reviewed medical records of 258 patients diagnosed with pediatriconset MS from 6 health care centers across the United States. These patients had to have received treatment with a first-line DMT for at least 6 months. The medical records were reviewed for 2 years, and clinical markers for disease progression were recorded.

The researchers found that approximately half of the children included in the study had their therapy changed to a second agent, owing to either refractory disease, poor tolerability of a first-line DMT, or noncompliance. Moreover, despite lack of robust evidence of safety and efficacy of second- line DMTs like mitoxantrone, natalizumab, cyclophosphamide, and rituximab in the pediatric population, these agents were routinely used.

This study shows that vigilance should be maintained when using second-line DMTs in the pediatric population and that future studies are needed to identify “optimal treatment strategies in pediatric MS.”

HLA Gene Variant More Likely Found in Women Than Men

While it is the general consensus that the incidence and prevalence of multiple sclerosis (MS) have recently been increasing more in women than in men, scientists have long been unable to explain why. Due to a new study published in January’s issue of Neurology, an explanation for this gender discrepancy may be on the horizon. Researchers from the University of Oxford designed a large family-based cohort study consisting of 7093 individuals from 1055 families with more than 1 member with MS. They examined the transmission of human leukocyte antigen (HLA) Class II genes, the main genetic contributor to MS. The MS families that were included consisted of 6 different types: affected sibling pair, parent-child, sporadic, aunt/ uncle—niece/nephew, cousin, and multiplex. All families were Canadian and of European descent. Genotyping for the affected HLA allele, HLA-DRB1*15, was performed. Scientists found the female-to-male ratio to be higher in cases with HLA-DRB1*15 transmission versus those without (χ2 = 9.97, P = 0.0015). Further, a significant difference of allele transmission was observed between nuclear and collateral families in affected female-female pairs, but not in affected female-male and affected male-male pairs.

Because the female-to-male ratio of MS incidence in North America was approximately 1:1 at the turn of the 20th century and is now 2:1 despite regional variations, the researchers argue that gene-environment interactions, and not genetic factors, are more likely responsible. Because this study demonstrated that individuals with HLADRB1* 15 have a significantly higher femaleto- male ratios compared with those without, gender ratio may become a fifth environmental factor interacting with the genome.