Systemic Sclerosis-Associated Interstitial Lung Disease: Current Insights and Future Directions

Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is a progressive and potentially debilitating pulmonary complication of systemic sclerosis (SSc). It is characterized by inflammatory and fibrotic changes in the lung parenchyma, significantly contributing to morbidity and mortality [1]. The clinical course of SSc-ILD varies widely, with some patients experiencing rapid disease progression and severe respiratory impairment, while others exhibit a more indolent trajectory. Despite advances in therapeutic interventions, no universally accepted treatment strategy for SSc-ILD exists, necessitating continued research into optimal management approaches.

The pathogenesis of SSc-ILD is complex, involving genetic predisposition, immune dysregulation, vasculopathy, and fibrosis [2]. Microvascular damage and dysfunction are the earliest morphological and functional indicators of systemic sclerosis (SSc), a progressive connective tissue disease marked by vascular abnormalities and widespread fibrosis, often initially presenting as Raynaud phenomenon [3]. Key profibrotic mediators include an imbalance in macrophage activation (M1/M2) and T-helper 2 (Th2)-polarized cytokines. Elevated IL-4 and IL-13 (traditionally “allergic” cytokines) with higher circulating mixed M1/M2 monocyte/macrophage cell percentages are associated with SSc-ILD [2, 4, 5]. IL-6, a pleiotropic cytokine, sustains chronic inflammation and links the early immune response to later fibrosis. These cytokines, together with potent fibrogenic growth factors like transforming growth factor-beta (TGF-β), create a profibrotic lung microenvironment. The interaction between endothelin/VEGF(Vascular Endothelial Growth Factor) signaling from injured vasculature and TGF-β is thought to be a pivotal trigger that converts quiescent fibroblasts into activated myofibroblasts, resulting in excessive extracellular matrix deposition and progressive fibrosis [1, 6].

Although no animal model of SSc-ILD fully replicates all pathological aspects of the disease, bleomycin-induced lung fibrosis remains a valuable tool and is extensively utilized to investigate the pathogenesis of SSc-ILD [7]. In the bleomycin model, initial lung injury is characterized by type I interferon (IFN) signaling activation, with subsequent TGF-β recognized as a pivotal driver of fibrosis [8]. As the disease progresses or is intervened upon, Th2 cells drive the formation of alternatively activated profibrogenic macrophages and collagen production [9].

Multiple clinical trials have shaped the management of SSc-ILD. Notably, inclusion criteria and patient characteristics vary across trials, which can impact outcomes and applicability to individual patients. To inform clinical decision-making, we summarize key trials' populations—including ILD patterns on imaging, disease duration, skin involvement, age, and comorbidities—in Table 1. SSc-ILD trials tend to enroll patients with relatively early disease (often < 5–7 years from onset) and evidence of ILD on HRCT(high-resolution computed tomography). A majority of participants have diffused cutaneous SSc (in trials focusing on SSc) and moderate lung impairment at baseline (mean FVC around 65%–80% predicted). These criteria enrich patients at risk of progression, but they may exclude those with very advanced fibrosis or long-standing disease. The median age in these studies is typically mid-50s, and the majority are female in some trials, reflecting SSc demographics. Notably, some trials allowed concomitant immunosuppressive therapy, whereas others did not, which can influence outcomes. Understanding these population differences is critical for clinicians when extrapolating trial results to individual SSc patients. Table 2 below summarizes the key evidence for major treatment strategies along with their findings and limitations.

An experimental approach in severe, refractory SSc-ILD is chimeric antigen receptor (CAR) T-cell therapy targeting B cells. Early results are encouraging. Schett et al. (2023) reported a case series of six patients with diffuse cutaneous SSc (all with ILD) treated with CD19 CAR-T cells [18]. Over 6–12 months, all patients' lung function stabilized, and some showed FVC improvement (median + 195 mL). High-resolution CT scans suggested slight regression of fibrotic changes (reduced ground-glass opacities). Skin fibrosis also improved, and autoantibody levels declined markedly. Similarly, an open-label pilot trial in Germany treated three patients with severe SSc-ILD using CD19 CAR-T: at 6 months follow-up, two patients maintained stable lung function and one patient's FVC increased by 390 mL (≈8%), with all three reporting clinical improvement [19]. It must be emphasized that CAR-T for SSc-ILD is in early-phase trials. Longer follow-up is needed to see if responses are durable and to monitor for delayed adverse effects. Ongoing studies (e.g., NCT05085444) will further assess safety and efficacy. CAR-T is also costly and requires specialized centers. Nonetheless, this approach represents a paradigm shift pointing out instead of chronic immunosuppression, a one-time cell therapy that induces long-term remission could become feasible.

Given the multifactorial pathogenesis of SSc-ILD, there is strong rationale to combine therapies that target inflammation and fibrosis or the combined use of two immunosuppressants. Emerging clinical evidence supports the use of such combination regimens. The Phase II SLS III trial investigated adding the antifibrotic pirfenidone to background MMF. Combination therapy led to a more rapid improvement in FVC within the first 6 months compared to MMF alone, and by 18 months, FVC gains were similar in both groups as both arms improved, but pirfenidone-treated patients showed favorable trends in fibrosis on HRCT and patient-reported functional outcomes [12]. However, tolerability remained an issue. The EVER-ILD trial addressed patients with CTD(connective tissue disease)-ILD and a NSIP(nonspecific interstitial pneumonia) pattern, reporting that the combination of rituximab and MMF was superior to MMF alone, though mentioning serious adverse events and infections [20]. Several ongoing and planned trials are investigating such multitarget strategies, and future studies will clarify the optimal timing (including upfront combination or sequential add-on) and pairing of therapies.

Future research in SSc-ILD should prioritize precision medicine approaches aimed at personalized therapy, emphasizing combination regimens and innovative treatments. Clinical trials assessing the efficacy and safety of combining immunosuppressive and antifibrotic agents are essential to establish optimal management strategies. Additionally, novel therapeutic modalities, such as CAR-T cell therapy targeting B cells, may induce durable remission rather than mere symptom control, warranting further rigorous clinical validation. The identification and clinical integration of biomarkers that accurately predict disease progression and treatment response will facilitate individualized patient care [21].

Current evidence supports specific medications as foundational treatments in SSc-ILD management. Immunosuppressants such as mycophenolate mofetil and cyclophosphamide remain primary therapies, with MMF generally favored due to a superior safety profile and comparable efficacy. Biologic therapies, particularly tocilizumab (TCZ), are beneficial in selected patients, particularly those with early inflammatory disease features, while rituximab (RTX) is a viable alternative to cyclophosphamide, especially in refractory or rapidly progressive cases. Nintedanib slows lung function decline and is suggested in patients who have failed standard management. However, robust clinical data for combination therapies are still emerging, and cautious patient selection based on individual characteristics and trial populations is crucial. Multidisciplinary collaborations integrating clinical, translational, and basic science research are imperative to advance treatment paradigms, including novel therapeutic options and biomarkers, ensuring comprehensive and real-world applicability for improved patient outcomes in SSc-ILD management.

All authors contributed to the design and implementation of the study and original draft preparation. Ming-Yuan Victor Chao and Po-Cheng Shih contributed equally to writing and revising the manuscript with critical support from Pui-Ying Leong, who provided critical feedback and helped revise the manuscript multiple times. All authors reviewed the results and approved the final version of the manuscript.

The authors declare no conflicts of interest.