TOPLINE:

In patients with systemic sclerosis-related interstitial lung disease (SSc-ILD), pirfenidone plus mycophenolate mofetil combination therapy vs placebo plus mycophenolate mofetil led to no significant improvement in forced vital capacity percentage (FVC%) over 18 months.

METHODOLOGY:

• Researchers conducted a randomized, placebo-controlled phase 2 trial of 51 adults with SSc-ILD (mean age, 54.7 years; 70.6% women) to assess the effect of combining mycophenolate mofetil with pirfenidone on improvement in lung function compared with the use of mycophenolate mofetil alone.
• Eligible participants had SSc with borderline restrictive lung disease (FVC%, ≤ 85%), symptomatic dyspnea, and ground glass opacities on baseline high-resolution CT (HRCT).
• Patients were randomly assigned to receive either pirfenidone plus mycophenolate mofetil (combination group; n = 27) or placebo plus mycophenolate mofetil (placebo group; n = 24). Participants received mycophenolate mofetil (up to 1500 mg twice daily) and pirfenidone (up to 801 mg three times daily).
• The primary endpoint was the change from baseline in mean FVC% over 18 months, measured at 3-month intervals.
• Secondary outcomes included changes over 18 months in lung diffusing capacity, skin thickness, dyspnea severity, patient-reported outcomes, and quantitative HRCT measures of lung disease.

TAKEAWAY:

• At 18 months, no significant difference in the change in FVC% was observed between the combination group and the placebo group, with a similar proportion of patients in both groups showing improvement in lung function.
• Compared with the placebo group, the combination group showed a significantly greater improvement in patient-reported physical function (P = .04) and numerically greater but not significant improvements in other patient-reported outcomes and HRCT measures at 18 months.
• More patients in the combination group than in the placebo group had adverse events of special interest (74.1% vs 29.2%).
• Eight patients in the combination group and two patients in the placebo group discontinued treatments early, with serious adverse events noted in four and two patients, respectively.

IN PRACTICE:

“Given the COVID-19 pandemic and other factors that substantially curtailed enrollment and impacted on statistical power, findings from SLS III [Scleroderma Lung Study III] cannot confirm whether there was any treatment advantage ,” the authors wrote.

SOURCE:

This study was led by Dinesh Khanna, MD, MSc, University of Michigan, Ann Arbor, Michigan. It was published online on November 26, 2025, in ACR Open Rheumatology.

LIMITATIONS:

The study enrolled only one third of the planned sample size, which reduced statistical power. Increasing adoption of mycophenolate mofetil as standard care affected recruitment of treatment-naive patients. The combination group had more early withdrawals and adverse events requiring dose adjustments. 

DISCLOSURES:

This study was supported in part by Genentech, including the provision of pirfenidone and placebo, but since the trial was investigator initiated, the company had no direct role in study design, data collection, data analysis, data interpretation, or writing of the report. Some authors reported receiving grants, research support, consulting fees, or honoraria; holding patents; or having other ties with various companies and organizations, including Genetech. One author reported being an employee of Bristol Myers Squibb. 

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.