The fibrosis puzzle of systemic sclerosis-associated ILD and the quest for targeted interventions

Abstract

Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is a leading cause of morbidity and mortality in systemic sclerosis, marked by complex immunopathogenic mechanisms and progressive fibrosis. Recent advances have illuminated key cellular players as T cells, macrophages, dendritic cells, and profibrotic mediators such as TGF-β, PDGF, and CTGF, alongside emerging roles for epigenetic reprogramming in sustaining fibroblast activation. This narrative review synthesizes current understanding of immune-fibrotic crosstalk and critically evaluates both established therapies (e.g., mycophenolate mofetil, nintedanib, tocilizumab, and rituximab) and novel targeted approaches. Particular attention is given to emerging immunomodulatory, antifibrotic, and cell-based therapies, including CAR-T and mesenchymal stem cell treatments, as well as the potential of epigenetic modulators repurposed from oncology. By bridging basic science and clinical practice, this review outlines the evolving therapeutic landscape of SSc-ILD and highlights opportunities for future research and personalized intervention.

Introduction

Systemic sclerosis (SSc) represents one of the most complex autoimmune rheumatic diseases, characterized by progressive fibrosis affecting the skin and internal organs, along with prominent microvascular dysfunction and immune system dysregulation. ¹ Among its diverse clinical manifestations, interstitial lung disease (ILD) emerges as the predominant cause of morbidity and mortality, occurring in approximately 60%–80% of patients and accounting for significant reductions in life expectancy.^2,3 In addition to fibrotic lung involvement, pulmonary hypertension (PH), including that secondary to SSc-associated ILD (SSc-ILD), represents a major complication and leading cause of death in this population, further compounding the clinical burden.^4,5 Despite advancements in understanding disease pathogenesis, SSc-ILD remains clinically challenging, and available treatments predominantly provide nonspecific immunosuppression with limited efficacy in reversing established fibrosis^6,7

Recent insights into the immunopathogenic mechanisms underlying fibrosis have reshaped our understanding of SSc-ILD, transforming it from a poorly defined phenomenon into a complex but increasingly decipherable pathological process.^8,9 Key discoveries have identified multiple cellular players, such as activated fibroblasts, myofibroblasts, and macrophages, orchestrated by critical profibrotic mediators, including transforming growth factor-beta (TGF-β), platelet-derived growth factor (PDGF), and connective tissue growth factor (CTGF).^10–12 Preclinical models have also helped elucidate the interplay between microvascular alterations, immune activation, and fibrogenesis in SSc.^13–15 Importantly, these emerging molecular pathways provide attractive targets for intervention, paving the way for precision therapeutics aiming at modulating specific pathological processes rather than broadly suppressing immune responses. ¹⁶

Nonetheless, the translational potential of these discoveries remains incompletely realized, with targeted therapeutic strategies still in varying phases of development and validation. Clinical trials assessing biologics, kinase inhibitors, and other novel molecularly targeted therapies have shown promise, yet their clinical impact and integration into multidisciplinary care are areas actively under exploration. ¹⁷ In parallel, considerable efforts are underway to identify robust biomarkers capable of predicting disease progression, therapeutic response, and prognosis, thus providing personalized and timely interventions.^18,19

The primary aim of this narrative review is to systematically analyze recent advancements in the immunopathogenesis and molecular mechanisms underlying fibrosis in SSc-ILD. Furthermore, it critically evaluates emerging targeted therapies currently in development and discusses the significance of multidisciplinary management approaches. By synthesizing evidence from bench to bedside, this review provides clinicians and researchers with an integrated, clinically relevant perspective on current and evolving strategies for managing SSc-ILD.

Search strategy

A comprehensive and methodologically rigorous literature search was conducted on the 15th of April to underpin this narrative review. ²⁰ The search involved major biomedical databases, including PubMed, Scopus, Web of Science, and Embase. Specific search terms were systematically formulated and combined using Boolean operators to cover essential thematic aspects, such as SSc-ILD, fibrosis, immunopathogenesis, targeted therapeutic interventions, biomarkers, and multidisciplinary management strategies. Examples of utilized keywords included “systemic sclerosis,” “SSc,” “interstitial lung disease,” “ILD,” “pulmonary fibrosis,” “immunopathogenesis,” “fibroblast activation,” “TGF-beta,” “PDGF,” “treatment,” “targeted therapy,” “biologics,” “small molecules,” “clinical trials,” “disease progression,” and “CAR-T.”

The search prioritized peer-reviewed original research articles, systematic reviews, meta-analyses, clinical practice guidelines, and expert consensus statements published primarily within the past decade, ensuring the inclusion of recent and relevant data. Seminal older studies were selectively included due to their foundational or landmark significance. Additionally, the reference lists of relevant articles were manually reviewed (“snowballing”) to identify further pertinent publications.

Studies were selected for inclusion based on their relevance, methodological quality, and contribution to understanding the immunopathogenesis, molecular mechanisms, therapeutic strategies, biomarkers, and multidisciplinary clinical management of SSc-ILD. Articles with insufficient methodological rigor, exclusively animal-based studies lacking clear translational significance, or papers primarily addressing unrelated fibrotic or autoimmune conditions were excluded.

The retrieved literature was systematically synthesized and critically evaluated to construct a cohesive and clinically applicable narrative. Two authors independently retrieved and screened the manuscripts, and any discrepancies or disagreements regarding inclusion were resolved through discussion with a third author. This structured approach was intended to provide clinicians and researchers with a current, evidence-based overview of emerging trends and best practices in the diagnosis, pathogenesis, and management of SSc-ILD, thereby guiding clinical decision-making and informing future research directions.

Immunopathogenesis and fibrogenesis

In SSc-ILD, a complex interplay of T cells, macrophages, and dendritic cells drives fibroblast activation and relentless extracellular matrix deposition in the lungs. ²¹ CD4⁺ T cells skew toward a Th2/Th17 phenotype, with Th2-derived cytokines (IL-4, IL-13) and Th17-derived IL-17 orchestrating profibrotic effects such as myofibroblast differentiation and collagen synthesis.^22–24 IL-17, often elevated in early SSc, can directly stimulate fibroblast proliferation and further amplify inflammation . ²⁵ Meanwhile, regulatory T cells (Tregs), which normally restrain autoimmunity via IL-10 and TGF-β, are numerically and functionally impaired. SSc Tregs show reduced suppressive capacity and may even transdifferentiate into IL-4/IL-13–secreting cells, exacerbating fibrosis rather than inhibiting it. ²³ The innate immune compartment is similarly skewed. M2-polarized macrophages infiltrate SSc-affected lungs and skin, releasing potent profibrotic mediators, including TGF-β, PDGF, and CCL18, which directly induce fibroblast activation and collagen overproduction.^26,27 Th2 cytokines (IL-4, IL-13) further promote macrophage M2 polarization, creating a feed-forward loop of fibrosis. Elevated insulin-like growth factor levels in SSc bronchoalveolar fluid (IGF-1 and IGF-2) also drive fibroblast proliferation and matrix deposition. ²⁸ Dendritic cells bridge innate and adaptive immunity by presenting autoantigens and secreting cytokines (e.g., IL-6, TNF-α, type I interferons) that skew T cells toward fibrogenic phenotypes. ²⁹ In parallel, persistent Toll-like receptor engagement by endogenous danger-associated ligands sustains a chronic inflammatory milieu. ³⁰ Unabated NLRP3 inflammasome activity in SSc lesions leads to continual IL-1β and IL-18 release, perpetuating immune cell recruitment and activating collagen-producing myofibroblasts.^31,32

Fibroblast activation and subsequent fibrogenesis in SSc-ILD involve multifaceted interactions among key molecular mediators and signaling pathways. Central among these mediators is TGF-β, recognized as a master regulator of fibrosis, which orchestrates fibroblast-to-myofibroblast differentiation and sustains the fibrotic phenotype through autocrine signaling loops.^33,34 PDGF further augments this process by promoting fibroblast proliferation and migration, significantly increasing the pool of fibroblasts capable of ECM deposition.^35,36 Concurrently, aberrant activation of the Wnt/β-catenin signaling pathway sustains fibroblast survival, differentiation, and functional persistence, creating a self-reinforcing cycle that perpetuates fibrosis. ³⁷

Recent investigations have also illuminated critical roles for epigenetic modifications and metabolic reprogramming in sustaining fibroblast activation.^38–40 Epigenetic changes, such as altered DNA methylation, histone modifications, and dysregulated microRNA expression profiles, effectively entrench fibroblasts in a profibrotic state. ⁴⁰ These epigenetic shifts lead to persistent activation of fibrosis-associated genes and suppression of antifibrotic regulatory mechanisms.

Targeted therapeutic interventions

Established therapeutic agents and clinical efficacy

Recent international guidelines, including those from EULAR, ⁴¹ the American College of Rheumatology (ACR), ⁴² and the British Society for Rheumatology (BSR), ⁴¹ underscore a stratified approach to SSc treatment, emphasizing early intervention tailored to organ involvement and disease progression. These recommendations endorse immunosuppressive agents such as mycophenolate mofetil (MMF), while also acknowledging the roles of targeted therapies such as nintedanib, tocilizumab, and rituximab in specific clinical contexts.

Mycophenolate mofetil

MMF is currently considered a first-line immunosuppressive therapy for SSc-ILD, supported by robust clinical evidence.^41–43 Its mechanism, based on the inhibition of lymphocyte proliferation, targets key immune pathways implicated in the pathogenesis of SSc-ILD. ⁷ A meta-analysis supported efficacy of MMF, showing that while the weighted mean difference (WMD) in forced vital capacity (FVC) change between MMF and cyclophosphamide was not statistically significant (WMD: −1.17; 95% CI: −2.713 to 0.373; p = 0.137), MMF was associated with a significantly greater improvement in diffusion capacity of the lungs for carbon monoxide (Dlco) (WMD: 2.245; 95% CI: 0.258 to 4.232; p = 0.027), indicating a potential advantage in preserving gas exchange capacity. ⁴⁴ In the Scleroderma Lung Study II, the adjusted FVC% predicted improved modestly over 24 months in both the MMF (2.17%; 95% CI: 0.53–3.84) and cyclophosphamide (2.86%; 95% CI: 1.19–4.58) groups, with no significant difference between them (p = 0.24), and quantitative High-resolution computed tomography (HRCT) scores showed minimal changes in fibrosis burden, with a slight reduction in whole-lung QILD scores in both treatment arms (−2.51 for MMF and −2.78 for CYC). ⁴⁵ However, MMF was better tolerated over 24 months and associated with fewer adverse events, including leukopenia and treatment discontinuation. ⁴⁵ Recent guidelines from the American Thoracic Society strongly recommend MMF for SSc-ILD, particularly in patients with risk factors for progression. ⁴⁶ Furthermore, MMF can serve as a backbone therapy for combination approaches in cases of progressive pulmonary fibrosis despite immunosuppression. ⁴⁷ Overall, MMF offers a clinically feasible and evidence-backed strategy for managing SSc-ILD in routine practice.

Tocilizumab

Tocilizumab has been shown to halt pulmonary function decline in SSc-ILD. In the phase III focuSSced trial, patients on tocilizumab experienced significantly less decline in lung function compared to those on placebo, with a minimal change in percent predicted FVC (0.07% vs −6.4%) and a substantially smaller drop in absolute FVC. ⁴⁸ Based on these findings, tocilizumab received FDA approval for the treatment of SSc-ILD. ⁴⁹ However, its use requires caution due to potential adverse effects, including an increased risk of infections (e.g., pneumonia and atypical pathogens) and laboratory abnormalities such as elevated liver enzymes and cytopenias. ⁵⁰ Therefore, appropriate monitoring and implementation of prophylactic measures are essential to ensure safe and effective long-term therapy.

Rituximab

Pathogenic B cells in systemic sclerosis contribute to both autoimmunity and fibrosis through autoantibody production and cytokine release. Rituximab, a B cell–depleting monoclonal antibody, has gained attention as a promising off-label treatment for SSc-ILD, supported by accumulating evidence from cohort studies and meta-analyses. ⁵¹ These studies suggest that rituximab may help stabilize or even modestly improve lung function, as measured by FVC, in affected patients. ⁵² A meta-analysis by Jang et al. demonstrated that rituximab significantly reduced the decline in FVC compared to conventional treatment (standardized mean difference (SMD): 0.65; 95% CI: 0.08–1.22; p = 0.03), although no significant improvement was observed in lung diffusing capacity. ⁵¹ A recent systematic review further indicated slower ILD progression and potential FVC gains with rituximab, although most data originate from uncontrolled studies with overall low certainty. ⁵² Despite this, no large-scale placebo-controlled trials have yet been completed to confirm efficacy. Rituximab is generally well tolerated, with serious adverse events being uncommon; most patients experience only mild infusion reactions and an increased risk of infections. ⁵³ However, repeated dosing may lead to hypogammaglobulinemia and opportunistic infections, highlighting the importance of ongoing infection surveillance and prophylactic strategies. ⁵⁴

Nintedanib

Nintedanib targets pivotal profibrotic pathways by inhibiting receptors for PDGF, VEGF, and FGF, which are involved in fibroblast activation. ⁵⁵ The SENSCIS trial established nintedanib as the first agent to significantly attenuate lung function decline in this population, reducing the annual FVC loss to −52.4 mL/year compared to −93.3 mL/year with placebo—approximately a 44% reduction. ⁵⁶ Importantly, nearly half of the trial participants were receiving background mycophenolate therapy, yet the benefit of nintedanib was consistent regardless of concomitant immunosuppression. ⁵⁶ While the drug slows fibrosis progression, it does not improve symptoms or skin sclerosis, underscoring its role as a disease-modifying agent rather than a symptom-relieving treatment. ⁵⁷ Nintedanib’s adverse event profile in SSc closely parallels that observed in idiopathic pulmonary fibrosis, with gastrointestinal disturbances—especially diarrhea—reported in up to 75% of patients. ⁵⁶ Therefore, proactive supportive care, including the use of antidiarrheal agents, dose adjustments, and regular monitoring of weight and liver enzymes, is essential to optimize adherence and therapeutic benefit. ⁵⁸

Pirfenidone

Pirfenidone, a therapeutic agent known for its antifibrotic properties, has shown potential in managing SSc-ILD. Initial clinical investigations demonstrated that pirfenidone is tolerable in patients with SSc-ILD, primarily when dose titration is carefully managed. ⁵⁹ Notably, the LOTUSS trial reported that despite frequent, predominantly mild adverse effects such as nausea, fatigue, and rash, pirfenidone was generally tolerated without significant interference from concomitant mycophenolate mofetil treatment. ⁵⁹ While these findings encourage consideration of pirfenidone in the therapeutic landscape of SSc-ILD, the observed lack of substantial improvement in pulmonary function or other exploratory outcomes necessitates cautious optimism regarding its efficacy.

Another randomized placebo-controlled pilot study found that pirfenidone did not yield significant improvements in lung function, physical performance, dyspnea, or skin manifestations compared to placebo. ⁶⁰ Moreover, evidence from preclinical research raises concerns about the potential exacerbation of underlying vascular and inflammatory pathology in SSc-ILD. A murine model demonstrated that despite reducing fibrosis, pirfenidone aggravated pulmonary inflammation, eosinophilia, and vascular damage, particularly in settings dominated by T-helper type 2 (Th2)-mediated inflammation. ⁶¹ Such adverse effects were linked to increased endothelial permeability and pro-inflammatory cytokine release, emphasizing that undesirable inflammatory interactions under specific pathological conditions might overshadow the beneficial antifibrotic impact. Therefore, while pirfenidone remains a promising candidate due to its antifibrotic properties, careful patient selection and individualized treatment approaches are critical.

Emerging and novel therapies

The therapeutic landscape for SSc-ILD has advanced considerably, yet significant unmet needs persist. Current treatments—whether immunosuppressive or antifibrotic—generally slow the disease course rather than reverse it. ⁶² Progressive lung fibrosis still leads to morbidity and premature mortality in many SSc patients despite therapy. ⁶³ A major future goal is disease reversal or remission, achieving not just stability but actual improvement in lung function and structure (Figure 1). This might require a combination of sequential therapies that target multiple pathogenic pathways. ⁶⁴

Figure 1.

Challenges in emerging therapies for SSc-ILD.

SSc-ILD, systemic sclerosis-associated interstitial lung disease.

Determining the optimal timing and sequencing of therapies is another pressing question. SSc-ILD is heterogeneous—some patients have an inflammatory phenotype while others have a dense fibrotic pattern. ⁶⁵ Tailoring treatment to this phenotype is an evolving art: for instance, an “inflammatory” ILD might respond better to aggressive immunosuppression first, whereas a primarily fibrotic ILD might warrant early antifibrotic therapy. ⁶⁶

Another future direction is preventive therapy. Currently, clinicians typically initiate treatment once ILD is established and causing functional impairment. An unmet need is identifying which patients with SSc are at the highest risk for developing ILD and intervening proactively. Studies show that certain clinical factors, ⁶⁷ biomarkers,^68–70 and imaging findings ⁷¹ can predict ILD development. In the coming years, we may see trials of “pre-emptive” therapy—for example, using a mild antifibrotic or immunotherapy in early SSc patients with high-risk profiles before significant lung damage occurs. The hope is to suppress the pathogenic process at inception, akin to how rheumatologists treat early rheumatoid arthritis aggressively to prevent joint damage. ⁷²

Mesenchymal stem cell (MSC) therapy

MSCs possess immunomodulatory and antifibrotic properties, secreting factors that dampen T-cell activity and promote tissue repair . ⁷³ Early-phase studies in connective tissue disease ILD suggest that IV infusion of allogeneic MSCs is safe and may stabilize lung function. ⁷⁴ In a phase I trial, 10 patients with refractory CTD-ILD (three with SSc) received MSC infusions with no infusion reactions or acute toxicity; at 6 months, pulmonary function and HRCT findings were stable in the majority, and some showed marginal improvement . ⁷⁴ Potential challenges for MSC therapy include ensuring consistent cell product quality, durability of response, and regulatory hurdles. ⁷⁵ Nonetheless, MSC-based therapies are a promising path, aiming to reset the immune-fibrotic balance in SSc-ILD in a manner personalized to the patient’s disease state.

Looking further ahead, regenerative medicine might play a role in truly curing SSc-ILD. While lung transplantation is a last resort for end-stage SSc-ILD, ⁷⁶ emerging approaches, such as bioengineered lung tissue or therapies based on induced pluripotent stem cells (iPSCs), are under investigation and may hold future potential. ⁷⁷ However, their clinical utility and timeline for application remain uncertain. In addition, autologous hematopoietic stem cell transplantation (HSCT) has already shown that resetting the immune system can lead to prolonged SSc remission and even improvement in lung function in severe cases .^78–80 The ASTIS, SCOT, and ASSIST trials demonstrated significantly improved event-free survival with HSCT compared to cyclophosphamide, albeit with considerable treatment-related risk.^78–80 The challenge is to capture HSCT’s benefit while minimizing risk—perhaps via better patient selection, gentler conditioning regimens, or adjunctive protective therapies.

Gene editing and epigenetic approaches

Advances in gene editing are opening exploratory pathways to treat fibrotic lung disease at the molecular level. CRISPR/Cas9 technology, for example, is being investigated in preclinical models to alter or silence profibrotic genes and pathways . ⁸¹ In pulmonary fibrosis models, CRISPR has been used to target mediators of epithelial–mesenchymal transition and pathological fibroblast activation. ⁸² While still far from clinical application in SSc-ILD, these approaches raise the possibility of precisely correcting or dampening the aberrant immune-fibrotic drivers in a patient’s cells. Unlike cell therapy, gene editing could offer a more permanent modification of disease mechanisms. However, significant challenges remain, including delivery of gene editors to lung tissue, off-target effects, and ethical considerations. ⁸³ Future research may focus on ex vivo gene editing—for instance, editing a patient’s own hematopoietic stem cells or T cells to reduce their fibrogenic potential before re-infusion. This is a nascent area, but it underscores the growing interest in high-precision, mechanism-driven interventions for fibrosis.

Moreover, several epigenetic drugs originally developed for oncology might now be explored as potential antifibrotic and immunomodulatory therapies in systemic sclerosis (SSc), given the overlap in pathological mechanisms. ⁸⁴ DNMT inhibitors, such as 5-azacitidine and decitabine, reverse hypermethylation of antifibrotic genes such as DKK1 and SFRP1 in SSc fibroblasts and have shown preclinical efficacy in reducing collagen synthesis and restoring Wnt signaling antagonism.^85,86

HDAC inhibitors (e.g., trichostatin A (TSA), vorinostat) demonstrate antifibrotic effects via inhibition of SMAD3 signaling and upregulation of p21, ⁸⁴ with givinostat already approved for other chronic fibrotic conditions, such as Duchenne muscular dystrophy. ⁸⁷ In the murine bleomycin SSc model, TSA prevented dermal fibrosis, significantly reducing extracellular matrix accumulation in vivo. ⁸⁸ These results indicate that HDAC inhibitors can reverse the profibrotic gene expression program. Moreover, selective knockdown of HDAC7 replicated the antifibrotic effect (reducing collagen I/III) without off-target upregulation of other profibrotic mediators. ⁸⁹ This suggests that targeting certain HDACs could modulate immune/fibrotic genes more precisely. Notably, HDAC inhibitors also exert immunomodulatory effects: in models of autoimmunity (e.g., lupus), HDAC blockade reduced inflammatory cytokine profiles and improved disease markers. ⁸⁴ This dual impact on inflammatory and fibrotic pathways makes HDAC inhibitors especially relevant to SSc’s combined immune-fibrotic pathology.

BET inhibitors, such as JQ1 and BRD4-selective compounds, downregulate fibrotic and inflammatory pathways in SSc models and may offer dual targeting of immune dysregulation and fibroblast activation. ⁹⁰ EZH2 ⁹¹ and LSD1 ⁹² inhibitors have also demonstrated promise in preclinical studies, though target specificity remains an ongoing challenge. Safety data from oncology use, particularly with low-dose or isoform-selective agents, suggest that epigenetic drugs could be repurposed for nonmalignant indications if immune effects are carefully managed. ⁸⁴ However, immune modulation remains a double-edged sword; while some epigenetic agents restore immune balance, others may trigger excessive interferon responses or autoreactivity. ⁸⁴

While none are currently approved for SSc, several agents are readily available and may be feasible for academic trials, especially in severe, treatment-refractory cases.^85,91,93 Given SSc’s refractory nature and lack of disease-modifying therapies, these drugs represent promising candidates for future investigation.

Autotaxin inhibitors

The lysophosphatidic acid (LPA) signaling axis has been implicated in SSc pathogenesis, linking fibrosis and inflammation^94,95 and autotaxin is an enzyme that generates LPA. ⁹⁶ In SSc patients, an “autotaxin–LPA–IL-6” amplification loop has been described, wherein LPA stimulates IL-6 release and promotes fibrosis. ⁹⁷ Ziritaxestat (GLPG1690) is a small-molecule autotaxin inhibitor that showed antifibrotic effects in early studies and was tested in clinical trials for both idiopathic pulmonary fibrosis and diffuse cutaneous SSc.^98,99 In a phase IIa SSc trial (NOVESA), ziritaxestat appeared safe and tolerable, but the development program was halted after the IPF phase III trials (ISABELA 1 and 2) were terminated for futility and safety concerns . ¹⁰⁰ Interim data indicated no meaningful efficacy and an unfavorable risk–benefit profile. ¹⁰⁰ This setback highlights the challenges in translating novel pathway inhibitors to clinical success, yet the LPA axis remains an attractive target. Researchers are now exploring alternative autotaxin/LPA inhibitors and LPA receptor blockers, as well as seeking patient subsets who might benefit from modulating this pathway. ⁶³

Antifibrotic monoclonal antibodies

Given the central role of transforming growth factor-beta (TGF-β) and other fibrogenic mediators in SSc-ILD, several biologic agents targeting novel pathways are under investigation. ²⁸ One of the examples is the integrin α_Vβ_6, which is expressed on injured lung epithelium and activates latent TGF-β. ¹⁰¹ Preclinical models showed that blocking α_Vβ_6 can prevent pulmonary fibrosis . ¹⁰² However, a humanized anti-α_Vβ_6 antibody (BG00011) recently failed in IPF: a phase II trial was stopped early due to excess acute respiratory worsening and death in the treatment arm . ¹⁰² This unexpected outcome suggests on-target toxicity (perhaps due to disrupting homeostatic epithelial–mesenchymal crosstalk) and tempers enthusiasm for systemic integrin blockade.

Other monoclonal antibodies under study include those targeting CTGF and IL-13/IL-4 signaling, which play significant roles in SSc fibrosis.^103,104 IL-17 and IL-23 axis inhibitors are currently under investigation to mitigate Th17-mediated inflammation, ¹⁰⁵ while TGF-β antagonists aim to interrupt the central profibrotic signaling cascade. ¹⁰⁶ In addition, novel immunoregulatory strategies such as low-dose IL-2 therapy seek to restore immune tolerance by enhancing regulatory T-cell function. ¹⁰⁷ These agents are in early-phase trials; if successful, they could complement existing therapies by specifically attenuating key profibrotic signals.

The common theme among emerging biologics is the pursuit of antifibrotic precision—intervening in downstream pathways that drive matrix deposition, while ideally sparing general immune function. Achieving this selectivity without undue side effects is the major challenge (Figure 2), as illustrated by the integrin trial experience.

Figure 2.

Future directions in SSc-ILD therapy.

SSc-ILD, systemic sclerosis-associated interstitial lung disease.

CAR-T cell therapy in SSc and SSc-ILD: A new frontier in treatment

Recent evidence suggests that chimeric antigen receptor (CAR)-T cell therapy, widely successful in B cell malignancies, may offer a potent new approach for refractory SSc, particularly in patients with SSc-ILD (Figure 3). The rationale stems from the prominent role of B cells in SSc pathogenesis, including autoantibody production and aberrant B cell activation, which contributes to fibrosis .^79,108 CAR-T cells engineered to target CD19 can achieve complete and prolonged B cell depletion, including elimination of CD20-negative plasmablasts that escape rituximab . ¹⁰⁸ Inspired by dramatic remissions in severe lupus after anti-CD19 CAR-T therapy , ¹⁰⁹ investigators have begun extending this strategy to SSc.

Figure 3.

CAR-T therapy for SSc-ILD.

SSc-ILD, systemic sclerosis-associated interstitial lung disease.

Early clinical reports, though limited in number, have demonstrated striking outcomes in severe SSc, even reversing organ damage previously considered irreversible. In one case, a patient with diffuse cutaneous SSc and multiorgan involvement (heart, lungs, and joints) achieved rapid improvement in skin thickening, arthritis, and cardiac function following CD19 CAR-T infusion, with autoantibodies (antinuclear and anti-RNA polymerase III) disappearing from the serum . ¹⁰⁸ Notably, after CAR-T treatment, this patient’s pulmonary fibrosis stabilized over 3–6 months—no further ILD progression was seen on high-resolution CT or pulmonary function tests . Another report described a young SSc patient with rapidly progressive ILD (NSIP pattern) despite standard immunosuppression who received third-generation CD19 CAR-T therapy. Within 6 months, lung function substantially improved and fibrotic lung lesions regressed on imaging . ¹¹⁰ This degree of pulmonary reversal is unprecedented in SSc-ILD, underscoring the deep remissions CAR-T cells can induce. In fact, across the few treated SSc patients reported to date, modified Rodnan skin scores fell markedly (often by 50% or more within 6 months) and measures of overall disease activity improved in parallel.^111,112 Equally important, patients were able to discontinue conventional immunosuppressive therapies post-CAR-T, maintaining drug-free disease control during follow-up . ¹¹⁰ Crucially, these clinical benefits have come without serious toxicity in the short term—CAR-T infusions were generally well tolerated, with at most mild cytokine release syndrome and no significant organ-related adverse events observed . ¹⁰⁸

Mechanistic studies provide insight into how CAR-T therapy is altering the disease trajectory in SSc-ILD. As expected, anti-CD19 CAR-T cells induce complete and sustained B cell aplasia within days, which in turn leads to a sharp drop in SSc autoantibody levels and circulating immune complexes .^108,112 This “autoimmune reset” appears to quell downstream drivers of fibrosis. For example, the disappearance of anti-topoisomerase (Scl-70) immune complexes after CAR-T was linked to a normalization of innate immune cell activity: previously over-activated natural killer cells in the patient reverted to a more quiescent, “juvenile” phenotype as immune complexes that engage their Fcγ receptors waned . ¹¹² Such findings suggest that CAR-T therapy interrupts the feed-forward loop of autoimmunity and innate inflammation that sustains tissue fibrosis in SSc. Consistent with this, treated patients showed not only serological remission but also objective reduction in fibroblast activation in affected organs. In one case, molecular imaging with a fibroblast activation protein inhibitor (FAPI) PET scan documented a one-third reduction in fibroblast activity in the myocardium just months after CAR-T, correlating with clinical cardiac improvement . ¹⁰⁸ By silencing pathogenic B cells, CAR-T cells thus indirectly dampen the profibrotic immune milieu, allowing aberrant tissue remodeling to pause or even recede. ¹¹³ Notably, immunoglobulin levels in patients have remained sufficient post-CAR-T (many did not require IVIG supplementation), and reconstitution of healthy B cells and other immune cells occurs within months ,^108,110 suggesting that immune homeostasis can be restored without prolonged immunodeficiency. These immune dynamics strengthen the view that B cells are central orchestrators of SSc pathology and that depleting them via CAR-T can induce a state of remission conducive to tissue repair.

Preclinical investigations both support and caution against certain extensions of CAR-T therapy in SSc-ILD. On one hand, novel CAR-T strategies targeting the fibrotic process directly have shown promise in experimental models. For instance, CAR-T cells directed against fibroblast activation protein (FAP) were able to significantly reduce cardiac fibrosis and improve cardiac function after injury in mice, without off-target toxicities in other organs . ¹¹⁴ This raises the intriguing possibility of deploying anti-fibroblast CAR-T cells to attack the resident profibrotic cells in SSc-ILD lungs or skin, potentially halting fibrosis at the source. CAR-modified regulatory T cells (CAR-Tregs) have also been proposed as a way to reinstate immune tolerance in SSc by delivering targeted immunosuppression to affected tissues . ¹¹⁵ This could ameliorate autoimmunity while sparing the rest of the immune system. On the other hand, disease complexity means outcomes can differ by context. An illustrative example is the Fos-related antigen-2 transgenic mouse, a model of SSc-like pulmonary fibrosis that lacks a strong autoantibody component . ¹¹⁶ In this model, aggressive B cell depletion using CD19 CAR-T cells unexpectedly worsened lung fibrosis and mortality . ¹¹⁶ The authors postulated that in the absence of pathogenic autoimmunity, the immunological perturbation of CAR-T cells might have triggered or failed to counter fibrogenic pathways . ¹¹⁶ Although not directly mirroring human SSc, this finding serves as a caution that the success of CAR-T therapy likely hinges on treating the right immunologic phenotype—patients whose fibrosis is indeed immune-driven. It underscores the importance of careful patient selection and further mechanistic research as we broaden the application of CAR-T in SSc.

Encouragingly, the initial clinical successes in SSc-ILD have spurred formal trials that are beginning to confirm safety and efficacy in larger settings. A recent phase I study employed an allogeneic (donor-derived) CD19 CAR-T product to treat three patients with severe, refractory autoimmune disease—two with diffuse cutaneous SSc and ILD, and one with an immune myositis—with remarkable results. ¹¹⁷ The gene-edited “off-the-shelf” CAR-T cells engrafted without provoking graft-versus-host reactions, achieving complete B cell depletion within 2 weeks and persisting for over 3 months . ¹¹⁷ Both SSc patients experienced deep remission of disease activity: over 6 months, their skin sclerosis and ILD manifestations improved substantially, accompanied by reversal of inflammatory and fibrotic damage in vital organs. Notably, no patient in this trial suffered cytokine release syndrome or other serious adverse events, highlighting that CAR-T therapy can be feasible and tolerable even in fragile SSc patients when carefully managed. These findings not only validate earlier case reports but also demonstrate the practicality of translating CAR-T therapy into a more accessible format (using banked allogeneic cells) for autoimmune diseases. Looking ahead, ongoing trials will shed light on the durability of remission induced by CAR-T in SSc-ILD and whether re-treatment or maintenance therapy is needed as B cells eventually return. Key questions—such as the optimal timing of intervention in the disease course, how to balance lymphodepletion for efficacy versus safety, and whether targeting other cell types (fibroblasts or pathogenic T cells) could further enhance outcomes—remain to be answered. What is clear already is that CAR-T cells can fundamentally reset the immune-fibrotic axis of SSc in a way no previous therapy has achieved, leading to genuine clinical improvement even in advanced ILD . ¹¹⁰ The coming years will determine how this experimental therapy can be integrated into SSc management, but its early success marks a pivotal shift in the therapeutic paradigm for systemic sclerosis.

Monitoring and follow-up in SSc-ILD

Effective monitoring and follow-up of SSc-ILD are critical components of clinical management, given the heterogeneous and potentially progressive nature of the disease. ¹¹⁸ Regular pulmonary function testing (PFT), primarily evaluating FVC and DLco, remains central to monitoring disease severity and progression. ¹¹⁹ A decline in FVC ⩾10% predicted or a combined decline in FVC (5%–9%) and DLco (⩾15%) over 6–12 months is indicative of clinically significant progression and necessitates careful re-evaluation of therapeutic strategies. ¹²⁰ However, clinicians should remain attentive even to smaller decrements in lung function, as these cumulative changes correlate with increased mortality risk.

HRCT serves as a cornerstone imaging modality in assessing both the baseline extent and progression of SSc-ILD. ¹²¹ Baseline HRCT findings such as a greater extent of fibrotic involvement (>20%–30% of the lung parenchyma), traction bronchiectasis, and honeycombing are associated with poorer prognosis and heightened risk of disease progression.^119,122 While HRCT provides essential prognostic information, its repeated use is tempered by concerns related to radiation exposure. Consequently, HRCT monitoring is recommended selectively, guided by clinical symptoms, significant changes in PFT results, or other clinical indicators of disease progression. ¹²¹ Low-dose HRCT protocols and advanced image reconstruction techniques (e.g., iterative reconstruction) may mitigate radiation risks while preserving diagnostic utility, particularly valuable in serial assessments. ¹²³

Additional modalities, such as lung ultrasound, while sensitive in detecting ILD, are less specific than HRCT and currently serve as supplementary rather than standalone monitoring tools. Emerging imaging methods, including magnetic resonance imaging (MRI) and positron emission tomography–computed tomography (PET-CT), show promise but require further validation in clinical practice. ¹¹⁹

The integration of multidisciplinary care has emerged as a crucial strategy in optimizing the management and improving outcomes for patients with SSc-ILD. ¹²⁴ Evidence consistently underscores the importance of collaborative interactions among rheumatologists, pulmonologists, radiologists, and allied health professionals to address both pulmonary and systemic manifestations comprehensively. Pulmonary rehabilitation programs effectively enhance exercise tolerance and reduce dyspnea, substantially improving patients’ physical functionality and quality of life. ¹²⁵ Psychological support addresses mental health burdens associated with chronic illness, reducing anxiety and depression, and consequently improving overall adherence and patient satisfaction. ¹²⁶ A patient-centered approach, considering individual disease characteristics and progression risk factors, ensures customized and effective follow-up care, ultimately aiming to improve outcomes and quality of life in patients with SSc-ILD.

Conclusion

SSc-ILD remains a significant clinical challenge, characterized by complex immunopathogenic mechanisms and persistent fibrotic processes. A deeper understanding of the intricate interplay between immune dysregulation, fibroblast activation, and fibrosis has shed light on promising therapeutic areas. Future research should prioritize comprehensive translational studies bridging basic science insights with clinical applicability and explore precision medicine approaches based on rigorously evaluated multidisciplinary care models in diverse healthcare settings.

For most patients, the future likely lies in incremental advances. The layering of targeted therapies guided by biomarkers and precision diagnostics, aiming to transform SSc-ILD into a manageable chronic condition rather than a fatal disease. Each of the interventions discussed, from biologics to gene therapy, contributes a piece to this puzzle. Robust clinical trials, international collaborations, and patient-centered outcome research will be vital to address the remaining questions and bring forth the next generation of SSc-ILD therapies.