A recent study published in Rheumatology (Oxford) has identified simple serum biomarkers that may help predict which patients with systemic sclerosis–associated interstitial lung disease (SSc-ILD) are most likely to benefit from rituximab therapy. In a post-hoc analysis of a randomized controlled trial, investigators found that baseline levels of C-reactive protein (CRP) and Krebs von den Lungen-6 (KL-6) were strongly associated with changes in lung function following treatment, with even minimal elevations in CRP linked to a favorable response.
The analysis used prospective data from 48 patients with SSc-ILD enrolled in the double-blind, randomized, placebo-controlled DESIRES trial. Rituximab, a monoclonal antibody targeting CD20-positive B cells, has been increasingly explored in SSc-ILD because of the central role of B cells in autoantibody production, cytokine release, and fibroblast activation that drive lung inflammation and fibrosis. However, response to rituximab has been heterogeneous in prior studies, highlighting the need for reliable predictors of benefit.
To explore treatment effect heterogeneity, researchers applied a machine-learning causal tree algorithm to 28 baseline clinical and laboratory variables, using change in percent predicted forced vital capacity (ΔppFVC) at 24 weeks as the primary outcome. CRP, a marker of systemic inflammation, and KL-6, a mucin-like glycoprotein released by injured alveolar epithelial cells and widely used as a biomarker of ILD activity, emerged as the most informative stratification factors, dividing patients into three subpopulations with distinct responses to rituximab compared with placebo.
Among patients with serum CRP levels ≥0.055 mg/dL, rituximab was associated with a significantly greater improvement in lung function than placebo, with a ΔppFVC difference of 8.01% (95% CI 4.40 to 11.62). In patients with CRP levels <0.055 mg/dL and KL-6 levels ≥364 U/mL, changes in ppFVC were similar between the rituximab and placebo groups, with a difference of 2.47% (95% CI –1.99 to 6.92). In contrast, in the subgroup with both low CRP (<0.055 mg/dL) and low KL-6 (<364 U/mL), rituximab was associated with a significantly lower ΔppFVC than placebo, with a difference of –6.85% (95% CI –10.80 to –2.91).
These results suggest that even low-grade systemic inflammation, as reflected by slight CRP elevations, may identify patients with more immunologically active disease who are more likely to respond to B-cell depletion. KL-6 adds complementary information by reflecting the degree of epithelial injury and ILD activity, helping to distinguish patients in whom inflammation rather than established fibrosis may be driving disease progression.
The findings are particularly relevant because current treatment decisions in SSc-ILD are often guided by clinical features and imaging rather than by validated predictive biomarkers. Recent guidelines increasingly support immunomodulatory therapy in patients with progressive or inflammatory phenotypes, and this study provides a practical, laboratory-based approach to refine patient selection. If confirmed in larger prospective cohorts, baseline measurement of CRP and KL-6 could be incorporated into routine assessment to guide personalized use of rituximab, optimizing benefit while minimizing unnecessary exposure in patients unlikely to respond.
Reference
Kuzumi A, Oba K, Ebata S, Kashiwabara K, Ueda K, Uemura Y, Watadani T, Fukasawa T, Miura S, Yoshizaki-Ogawa A, Kage H, Sato S, Yoshizaki A. Predictors of rituximab efficacy in systemic sclerosis-associated interstitial lung disease: machine-learning analysis of the DESIRES trial. Rheumatology (Oxford). 2025 Dec 1;64(SI):SI114-SI121.