Precision Medicine Benefits Patients with Systemic Sclerosis

Enabling early diagnosis & informed decision making

WASHINGTON, D.C.—Although most medical treatments are designed for the so-called average patient and use a one-size-fits-all approach, precision medicine seeks to tailor treatment to individuals based on their genes, environment, lifestyles and a host of other factors unique to them. At ACR Convergence 2024, the session titled, State of the Art Lecture: Precision Medicine in Systemic Sclerosis, brilliantly applied the concepts behind precision medicine to the care of patients suffering from scleroderma.

Very Early Diagnosis

Dr. Del Galdo

The first speaker was Francesco Del Galdo, MD, professor of experimental medicine (consultant), head of scleroderma program at the Leeds Institute of Rheumatic and Musculoskeletal Medicine, Leeds, U.K. Dr. Del Galdo is the current president of the European Scleroderma Trials and Research Group (EUSTAR) and, in this capacity, has been at the forefront of helping establish criteria for the very early diagnosis of systemic sclerosis (VEDOSS).

In 2011, the preliminary criteria for VEDOSS were first developed using a Delphi model among international experts on scleroderma. These criteria included several different domains, including skin (i.e., puffy fingers/swollen digits turning into sclerodactyly); vascular (i.e., Raynaud’s, abnormal capillaroscopy with scleroderma pattern) and laboratory (i.e., antinuclear, anticentromere and antitopoisomerase-I antibodies).¹

In 2021, the VEDOSS criteria were updated, making the only mandatory, first-step criterion to be evaluated the presence of Raynaud’s phenomenon. Using this approach, the combination of Raynaud’s phenomenon associated with antibodies specific to systemic sclerosis—and anti-nuclear antibody positivity—and puffy hands had the highest risk of progression to meeting the 2013 ACR/EULAR classification criteria for systemic sclerosis (i.e., 94% of patients with these criteria ultimately progressed).¹

Dr. Del Galdo explained that having a robust and validated definition for VEDOSS is important so as not to miss patients who are early in their course of disease. He pointed out that pulmonary hypertension may develop up to 10–15 years after the initial onset of disease.² Dr. Del Galdo also noted that, for a patient to have a mean pulmonary arterial pressure of ≥25 mm/Hg on right heart catheterization—therefore meeting the definition of pre-capillary pulmonary hypertension from the 2022 European Society of Cardiology and European Respiratory Society—more than 50% of alveoli need to be affected by the patient’s disease.

Although clinicians are quick to think of digital ulcers and telangiectasias as signs of scleroderma, musculoskeletal and gastrointestinal symptoms may actually be among the first non-Raynaud’s symptoms found in patients with severe skin disease. Thus, clinicians may fail to ask about these symptoms or identify signs of involvement on the physical exam, thereby missing the opportunity to reduce diagnostic delay for patients.

Dr. Del Galdo went on to discuss what we have been learning from biosamples collected from VEDOSS patients. In one study, the sera from 64 patients with VEDOSS were tested for interferon (IFN) inducible chemokines. These results were compared with those of healthy controls and patients with systemic sclerosis. The study found that levels of these chemokines were significantly higher in patients with VEDOSS than healthy controls and were at intermediate levels when compared with patients with systemic sclerosis. Skin punch biopsies were also collected from all three study groups, and those from patients with VEDOSS demonstrated evidence of fibrosis and increased collagen bundles within the dermis commensurate with that typically seen in patients with systemic sclerosis.³  

The totality of these data suggests that it’s possible to accurately identify patients who are at high risk of progressing to systemic sclerosis and that future disease-modifying treatments should be employed in this therapeutic window.

ILD & Patient Care

Dr. Volkmann

The second speaker was Elizabeth Volkmann, MD, MS, associate professor of medicine, director of the UCLA Scleroderma Program and the founder and co-director of the UCLA Connective Tissue Disease-Related Interstitial Lung Disease (CTD-ILD) Program, UCLA School of Medicine. Dr. Volkmann explained that a fundamental problem in the field is that ILD is the leading cause of death in patients with systemic sclerosis. Although there is an increasing number of therapies to treat this condition, including mycophenolate mofetil, cyclophosphamide, nintedanib, tocilizumab and rituximab, we lack the tools needed to make informed treatment decisions in these cases.

Regarding when to start therapy for ILD, Dr. Volkmann noted that many clinicians take a watch-and-wait approach, in which therapy is only initiated when there is evidence of disease progression. However, taking this approach and relying on such measures as forced vital capacity (FVC) and high-resolution computed tomography (HRCT) chest imaging wastes precious time and risks having the patient accrue irreversible lung damage.

In terms of predicting the risk of ILD progression, Dr. Volkmann explained that we mostly rely on clinical features (i.e., the patient’s gender, race, antibody status, degree of cutaneous involvement and disease duration). But these features do not consistently predict outcomes in individual patients. It is also hard to predict when a patient has both a risk factor for progression and a protective factor that may lessen the likelihood of progression.

Dr. Volkmann clearly stated that, as of this moment, no valid prognostic or predictive biomarkers exist for scleroderma-associated ILD (SSc-ILD). She noted that a prognostic biomarker is a clinical or biological characteristic that provides information on the likely patient health outcome, such as disease progression or mortality, irrespective of the treatment. A predictive biomarker, on the other hand, is a characteristic that identifies individuals who are more likely to respond to a particular intervention.

One candidate prognostic biomarker for SSc-ILD is Krebs von den Lungen-6 (KL-6). KL-6 is a molecule that is predominantly expressed by damaged alveolar type II cells. In 2024, a study evaluated the prognostic potential of this circulating biomarker for FVC decline and change in modified Rodnan skin score (mRSS) over 52 weeks in the placebo group of the SENSCIS trial. In the 288 patients who received placebo, a baseline KL-6 ≥1000 U/mL was associated with lower median FVC% predicted and higher median mRSS than subjects with KL-6 <1000 U/mL. Additionally, higher baseline levels of KL-6 were associated with a greater rate of decline in FVC over 52 weeks.⁴

Dr. Volkmann’s hope is that studies like this one will help to identify and validate prognostic and predictive biomarkers for patients with SSc-ILD, enabling the highest risk patients to receive treatment early in their disease course.

The session was excellent and indeed represented the best ideas in line with precision medicine. Patients with scleroderma, and SSc-ILD in particular, are still suffering from mortality rates that remain stubbornly high, thus, sessions such as this one are necessary to bend the curve and improve care for patients around the world

Jason Liebowitz, MD, is an assistant professor of medicine in the Division of Rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York.

References

1. Avouac J, Fransen J, Walker UA, et al. Preliminary criteria for the very early diagnosis of systemic sclerosis: Results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group. Ann Rheum Dis. 2011 Mar;70(3):476–481.
2. Steen V, Medsger TA Jr. Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum. 2003 Feb;48(2):516–522.
3. Ross RL, et al. Biosamples from VEDOSS patients show classic pathological signs of Scleroderma: Opportunity for a biological diagnosis of disease. Br J Rheumatol. 2023 April;62(2).
4. Assassi S, Kuwana M, Ittrich C, et al. Prognostic value of circulating biomarkers in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). Ann Rheum Dis. 2024;83:332.