Precision medicine in systemic sclerosis: back to the bedside

Systemic sclerosis (SSc) is a highly heterogeneous disease with respect to clinical manifestations, disease severity, progression, and treatment response. ¹ This heterogeneity complicates both clinical management and therapeutic development, underscoring the need for improved patient stratification.

Precision medicine aims to tailor treatment and prevention strategies by accounting for inter-individual variability. In SSc, this approach is particularly relevant because conventional classification systems, largely based on skin involvement and autoantibody status, only partially reflect the complex spectrum of pathophysiological mechanisms, clinical trajectories, and therapeutic responses. ²

The four articles included in this special collection highlight important and often overlooked determinants of disease heterogeneity, emphasizing their implications for both clinical management and future research.

A comprehensive review of sex differences in SSc highlights that sex-related disparities extend far beyond differences in incidence. ³ Although women are more frequently affected, ⁴ men often experience more severe disease, including diffuse cutaneous involvement, interstitial lung disease, and poorer survival. ⁵ These disparities likely arise from a complex interplay of sex hormones, X chromosome biology, immune regulation, and fibrotic pathways. Importantly, gender-related factors, involving social roles, health behaviors, and access to care, may also contribute to diverse trajectories, although these aspects remain insufficiently studied in SSc.

One key dimension of sex-related differences in SSc relates to the role of sex hormones, particularly hormonal transitions across the life course. ⁶ The analysis from the SPRING-SIR registry further refines this perspective by examining menopausal status within a temporal framework of disease onset. ⁷ Menopausal status, age at menopause, and the timing of SSc onset relative to menopause were all associated with meaningful differences in clinical phenotype. In particular, post-menopausal disease onset was associated with limited cutaneous disease, anti-centromere antibody positivity, interstitial lung disease, and gastrointestinal involvement, whereas pre-menopausal onset was associated with diffuse cutaneous involvement and peripheral vasculopathy. In addition, early menopause emerged as an independent risk factor for vascular complications, including digital ulcers. Incorporating reproductive history into clinical phenotyping could therefore improve risk stratification in SSc.

As highlighted in this work, the timing of disease onset represents another clinically accessible yet underutilized dimension of precision medicine. The second SPRING-SIR study further expands this concept by showing, from a complementary perspective, that the sequence and timing of Raynaud’s phenomenon (RP) relative to the first non-Raynaud manifestation carry important prognostic information. ⁸ Patients with simultaneous onset of RP and non-RP manifestations had more diffuse cutaneous disease, more frequent anti-topoisomerase I positivity, higher modified Rodnan skin scores, and increased mortality compared with those in whom RP clearly preceded other features. These observations suggest that disease chronology may reflect distinct pathogenic trajectories.

Taken together, the two SPRING-SIR analyses highlight disease chronology as a clinically meaningful precision medicine tool. Whether considering the menopausal transition or the temporal relationship between RP and subsequent disease manifestations, both studies use the timing of disease events as a stratification tool. This temporal dimension represents an easily accessible yet largely underexplored approach to patient stratification in SSc.

The review on cardiac involvement in SSc adds a critical organ-specific perspective. ⁹ Cardiac involvement remains one of the leading causes of mortality in SSc, ¹⁰ yet often progresses subclinically. ² The proposed interdisciplinary cardio-rheumatology model combines multimodal vascular and cardiac evaluation. This model is intended for early screening and cardiac risk stratification of SSc patients. By linking microvascular dysfunction with downstream cardiac injury, this approach aims to identify patients at risk earlier in the disease course, even in the absence of cardiac symptoms. Integration of imaging data with artificial intelligence tools may further refine risk prediction and facilitate individualized surveillance strategies. Such interdisciplinary models exemplify how precision medicine can emerge from integrating clinical expertise, imaging technologies, and data-driven approaches.

First, taken together, these studies suggest that future registries and observational cohorts should systematically collect information on menopausal history, reproductive factors, and the timing of first disease manifestations, as these data are currently documented inconsistently. A minimal dataset could therefore include the following: menopausal status, age at menopause, age at first disease manifestation, pregnancy history and hormonal exposure. Standardizing these variables across registries would facilitate future longitudinal studies examining the relationship between reproductive aging and SSc onset, phenotype, and progression. Second, clinical trials should move beyond considering sex as a simple adjustment variable and begin exploring sex-, gender-, and life-stage-specific treatment effects. Third, interdisciplinary care models represent an important infrastructure for improved patient care.

At a time when precision medicine is increasingly driven by the identification of molecular signatures, multi-omics approaches, and proteomic profiling, this special collection reminds us of the importance of returning to the patient bedside. Factors such as sex and gender, reproductive history, disease chronology, and vascular and cardiac phenotypes are not only biologically meaningful but also readily accessible in daily practice, allowing immediate integration into clinical decision-making. Even in an era dominated by sophisticated biomarkers, careful clinical observation, supported by interdisciplinary collaboration and complementary clinical expertise, remains a cornerstone of precision medicine in SSc. In this regard, the collection also represents a compelling call to action for rheumatologists to refine their clinical observation skills, with a key strength lying in the redefinition of precision medicine as a discipline that begins with a thorough patient history.