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During nintedanib (Ofev) treatment for interstitial lung disease associated with systemic sclerosis (SSc-ILD), clinicians prescribing the drug should be watchful for an unusual, indirect side effect, trial data suggested.

Among patients participating in the pivotal SENSCIS trial that compared nintedanib with placebo for SSc-ILD, more than four times as many patients assigned to the active drug developed signs of malnutrition over 1 year of treatment as did those on placebo (4.5% vs 1.0%), according to Elizabeth Volkmann, MD, MS, of the University of California Los Angeles, and colleagues.

The problem appeared to stem from nintedanib's gastrointestinal (GI) side effects, such as diarrhea and nausea, the group explained in .

"Management of disease manifestations and gastrointestinal adverse events that may be associated with weight loss is important to reduce the risk of malnutrition in patients with SSc-ILD treated with nintedanib," they wrote.

Clinically, they added, the implication is that patients should be monitored for possible development of malnutrition. They should be told about the potential for GI side effects and given advice for their management, including "dose adjustment, treatment interruption, and/or use of therapies to relieve symptoms." Patients should also weigh themselves regularly.

Weight loss had been observed to be more common with nintedanib than placebo in the primary 52-week SENSCIS analysis. The rates were 10% versus 3%, respectively, . With additional data from an , rates through 100 weeks were 13.5% and 5.2%, respectively.

Nintedanib's label lists weight loss as an "adverse reaction," along with various GI complaints and decreased appetite. But weight loss severe enough to be deemed malnutrition was not initially noted.

In the new study, Volkmann and colleagues pointed out that three-quarters of nintedanib patients in SENSCIS reported diarrhea during the study, compared with 32% of the placebo group. "Most cases ... were of mild or moderate intensity" and didn't require treatment discontinuation, the researchers wrote.

To see if nintedanib was associated with an increased risk of malnutrition in patients with SSc-ILD, they conducted a post hoc analysis of 52-week SENSCIS data. The trial randomized 576 patients in equal numbers to nintedanib at 150 mg/day or placebo.

Volkmann and colleagues used a modified version of the to identify patients at risk for malnutrition, both at baseline and after 52 weeks of treatment. MUST scores people on the following factors:

• Body mass index in three categories (≥20, 18.5-20, <18.5)
• Weight loss as a percentage of baseline weight (<5%, 5-10%, >10%)
• Hospitalization for an adverse event during which parenteral nutrition was provided

Points are allocated for each and summed, with a maximum of 6 points possible. Volkmann and colleagues considered any score of 2 or higher as high risk for malnutrition; a score of 0 was low risk.

Most patients were at low risk at baseline, and most of them remained so during the study. Specifically, 74.0% of the nintedanib group were classified at low risk both at enrollment and at 52 weeks; this was also the case for 78.1% of the placebo group.

However, among nintedanib patients classified as low risk at baseline, 4.5% amassed 2 or more MUST points during the study and thus were rated at high risk, compared with 1.0% in the placebo group.

The researchers looked for baseline factors that might help identify patients at special risk for developing malnutrition but did not find any. Patients with low initial BMI (20 or less) were not more likely to develop malnutrition-related adverse events (although skin ulcers were markedly more common, irrespective of treatment). Weight loss while on nintedanib was actually less frequent with low BMI, at 4.2% versus 12.5% with higher BMI.

One issue might be that the mechanism of nintedanib's GI effects remains unknown. Volkmann and colleagues said it might be that the drug, a tyrosine kinase inhibitor, acts against vascular endothelial growth factor receptor expression, leading to "morphometric" changes in the GI tract that decrease gut motility. "At present, it is not possible to predict gastrointestinal side effects, or their severity, in an individual patient treated with nintedanib," the group wrote.

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