Severe attack, relapse rate predict poor azathioprine, MMF response

Both medications have been traditionally used off-label for NMOSD

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by Andrea Lobo |

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A severe attack or a higher annual relapse rate before starting azathioprine or mycophenolate mofetil (MMF) was associated with a poor response in people with neuromyelitis optica spectrum disorder (NMOSD), a small study shows.

An unsatisfactory response to either treatment, defined as a severe relapse or two or more nonsevere relapses within a year, occurred in more than half the patients in the study. Black patients were less likely to have a poor response to either immunosuppressant.

“Prediction of nonresponders could help determine which patients are most likely to benefit from newer … antibody treatments from the outset,” the researchers wrote in “Predictors of azathioprine and mycophenolate mofetil response in patients with neuromyelitis optica spectrum disorder: A cohort study,” which was published in Multiple Sclerosis and Related Disorders.

NMOSD is an autoimmune disease where the immune system launches an inflammatory attack that damages healthy cells in the brain and spinal cord. This mainly leads to transverse myelitis, or inflammation of the spinal cord, and inflammation of the optic nerve (optic neuritis), which transmits signals from the eye to the brain. This results in symptoms like vision and problems with muscle control. The disease is commonly marked by episodes of inflammation that reoccur periodically — relapses — separated by periods of remission when symptoms ease.

Treatment consists of immunosuppressives, mainly to delay or prevent disease attacks. Azathioprine and MMF have been traditionally used off-label for NMOSD, with observational studies showing their effectiveness. The medicines continue to be used in “resource-limited countries,” despite new therapies being approved.

“A priori knowledge of a patient’s likelihood to respond favorably or unfavorably to AZA [azathioprine] or MMF could help personalize and rationalize high-cost treatments,” wrote researchers in Brazil and the U.K. who analyzed data from 80 NMOSD patients from Brazil and 23 from the U.K. to identify predictors of response to the therapies.

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Response to azathioprine, MMF

The patients were mainly women (83.5%) and Black (65%). Their mean age at disease onset was 38 and they’d lived with the disease for a median of 5.4 years. The first symptom was transverse myelitis in about a third of the patients and optic neuritis in a quarter. Most participants (74%) had antibodies against the AQP4 protein, the most common type of NMOSD-driving self-reactive antibody.

During the follow-up, which lasted a median of 2.5 years, 44% of the patients treated with MMF and 45% of those on azathioprine remained free from relapses. Overall, 55% of all the patients had one or more relapses after at least four months on one of the treatments. Moreover, 42% were considered to have an unsatisfactory response — 65% due to a severe relapse and 35% due to two or more nonsevere relapses in a year.

A significantly greater proportion of patients with an unsatisfactory response had a severe relapse before treatment started than those with a satisfactory response (76.7% vs. 31.1%). Those with a poor treatment response also tended to be younger at disease onset (35 vs. 40).

Having a severe attack or having one or more attacks per year before starting either treatment were independent predictors of an unsatisfactory response, a statistical analysis showed that accounted for potential influencing factors.

Specifically, those with a previous severe relapse had a threefold higher risk of not responding to treatment, while those with an annualized relapse rate, or ARR, of one or more had a nearly five times increased risk.

Survival rates were also significantly different between those with or without a previous severe relapse and between those with or without at least one relapse in the previous year.

Moreover, having a Black ethnicity was associated with a 61% lower risk of a poor response to azathioprine or MMF treatment. These findings suggest that “Black ethnicity may be a protective factor before starting an immunosuppressant,” wrote the researchers, who noted “there was no sample size calculation for these results and they must be taken cautiously.”

“A larger multicenter study may explain this issue with a higher level of certainty,” they said.

When the team conducted the analyses with only patients with anti-AQP4 antibodies, only the significant association between one or more attacks a year before starting treatment and poor treatment response was maintained.

“In patients with NMOSD, almost half had unsatisfactory responses to AZA or MMF during a long follow-up. Severe initial attack and a [higher than one] ARR before starting these drugs were associated with this poor outcome,” the researchers wrote. “These findings suggest that these characteristics could guide the prescription of higher efficacy drugs.”