Year: 2024
Type: editorial
Abstract: This editorial refers to Distinct clinical trajectories of gastrointestinal progression among patients with systemic sclerosis, by Perin et al. Rheumatology, 2025;64:2766–74. The gastrointestinal (GI) tract is affected in over 80% of SSc patients, and is the third leading cause of death and a major cause of morbidity [1]. Manifestations of GI involvement vary greatly in terms of severity and progression, ranging from oesophageal dysmotility to severe malabsorption, and can occur at any stage of the disease [2]. Recently, a patient survey reported that GI involvement significantly impairs quality of life in 72% of cases, with 84% experiencing moderate-to-severe impact [3]. This highlights the urgent need to better understand the mechanisms of GI involvement and to develop effective treatments to maintain and ameliorate patients’ well-being. In SSc, despite the high prevalence of GI involvement significant gaps remain in our understanding of its pathogenesis, progression and treatment. The mechanisms that drive the variability of GI manifestations are not fully understood, especially regarding the interactions between immune and fibrotic processes in the GI tract—an area further complicated by the lack of animal models. Clinically, it is widely believed that GI involvement progresses in a cranio-caudal pattern, but there is a lack of reliable markers to identify which patients are at greater risk of severe progression or are likely to develop more serious complications. This makes the stratification of patients a persistent challenge. Additionally, treatment options are largely symptomatic, with limited evidence guiding the use of immunosuppressive therapies to modify the disease process in the GI system. The work of Perin et al. on the data from the Johns Hopkins Scleroderma Center Research Registry has opened a new window on the GI involvement by identifying distinct GI trajectories in SSc patients [4]. Previous studies have used cross-sectional analyses to identify patient subgroups based on GI involvement [5, 6], but only a snapshot in time could be captured, thus failing to disclose the dynamic nature of disease progression. Instead, Perin et al. [4] employed a longitudinal clustering approach overcoming this limitation by analysing the progression of GI disease over time on a database with a follow-up period spanning three decades, allowing a better understanding of the disease evolution. In fact, the study retrospectively analysed the clinical records of 2696 patients evaluating the GI involvement with the Medsger GI severity score across at least two available time points. Four distinct GI trajectories were identified: ‘Stable’, ‘Early Progressive’, ‘Late Progressive’ and ‘Early Severe GI’, which differed in severity, progression and association with other clinical features and autoantibody profiles. The two more severe clusters, ‘Early Severe GI’ and ‘Early Progressive’, were characterized by higher mortality rates and were more frequently associated with diffuse cutaneous subset, myositis and anti-fibrillarin antibody positivity. This latter finding is particularly noteworthy as it sheds light on a novel autoantibody already linked to severe GI manifestations. Thus, the study by Perin et al. suggests that anti-fibrillarin antibodies could serve as potential biomarker, identifying a subset of patients at higher risk for GI complications who may benefit from more comprehensive screening. The observed connection between anti-fibrillarin positivity and a greater burden of GI involvement may also indicate a possible pathogenic role in the development of these complications [7], highlighting the need for further studies exploring its cellular mechanisms. The ‘Late Progressors’ clusters were more often associated with the limited cutaneous subset and anti-Topoisomerase I antibody positivity, both of which are known to be linked with vascular complications [8] that in this group may drive the progression of GI involvement. This hypothesis may open the door to cellular studies to confirm this association within this specific subgroup. On the other hand, ACA and anti-RNA polymerase III antibodies were evenly distributed across the four clusters, appearing in 21–35% and 9–17% of patients, respectively. Although these antibodies have been linked to GI involvement in previous studies [9], they do not seem to be useful in predicting different progression trajectories. However, this highlights the importance of exploring the potential pathogenic role of autoantibodies, including their involvement in gastrointestinal issues, like anti-M3 muscarinic receptor antibodies or anti-vinculin antibodies [10]. Although Perin et al. investigated GI progression in a large cohort of patients, one of the main limitations of the study is its reliance on the Medsger severity index, which primarily measures severity based on symptoms. While this index provides a general assessment of GI involvement, it does not differentiate which specific segments of the GI tract are affected, thus limiting the depth of the analysis. The lack of instrumental data (e.g. endoscopy, manometry) further restricts the ability to fully characterize the extent and nature of GI involvement in the cohort. Additionally, the absence of detailed information on concurrent immunosuppressive therapies makes it difficult to evaluate the potential beneficial or adverse effects of these treatments on GI outcomes. It is well known that many treatments used to manage other major organ involvements in SSc can have GI side effects, potentially introducing bias in the assessment of symptoms. Furthermore, Perin et al. did not address the potential immunosuppressive benefits reported in other studies for reducing GI progression [11]. This is particularly relevant since the latest ACR/EULAR 2024 guidelines do not currently recommend immunosuppressive therapy for managing GI involvement [12]. Despite these limits, the study of Perin et al. in SSc has opened a new avenue in defining different GI trajectories which can stimulate further research works and can be useful in clinical practice. By distinguishing between GI subgroups with different risk profiles and disease courses, physicians can approach more consistently the GI problems in SSc patients. In the future, clinical trials could be designed with greater precision, targeting therapies to those most likely to benefit. This new approach holds the promise not only for improving patient outcomes but also for discovering new therapeutic strategies that might address the underlying mechanisms of GI involvement in SSc. Understanding these trajectories could be the key to tailoring treatments, moving beyond a one-size-fits-all approach to a more nuanced and effective management strategy. No new data were generated or analysed in support of this article. No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article. Disclosure statement: The authors have declared no conflicts of interest.
Source: Lara D. Veeken
Authors: Francesco Bonomi, Giulia Bandini, Serena Guiducci, Marco Matucci-Cerinic, Silvia Bellando Randone
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4405801955