Early progression of systemic sclerosis: a longitudinal cohort study on disease evolution and microvascular changes

Abstract

Objectives

This study aimed to evaluate the time from early-stage systemic sclerosis (SSc), to the onset of significant disease progression. A secondary objective was to identify early clinical features most strongly associated with disease progression. Additionally, the study examined the course of microvascular changes over time.

Methods

In this prospective longitudinal cohort study (Hit Hard and Early trial, 3 years open label follow-up), we included patients who met the adjusted Very Early Diagnosis of Systemic Sclerosis criteria, with puffy fingers for less than 3 years. Disease progression was defined as skin or organ involvement. Microvascular changes were tracked through serial nailfold videocapillaroscopy, and Kaplan-Meier estimates were used to analyse time to disease progression. Baseline predictors of progression were explored with univariate logistic regression.

Results

Thirty patients were included, 70% female, with a median duration of puffy fingers of 5.5 months. Anticentromere antibodies were present in 73%, and 75% showed an active nailfold capillaroscopy pattern at baseline. Over 3 years, 43% (95% CI: 25.6%-61.2%) developed clinically significant disease progression, predominantly manifesting as pitting scars, digital ulcers, and/or skin thickening. Mean capillary density declined over time, and 55% of patients with an early SSc capillaroscopy pattern progressed to an active or late pattern within 24 months.

Conclusions

A large proportion of patients showed clinically relevant disease progression within 3 years. In spite of the limited sample size, the strong association between anti–ribonucleoprotein (anti-RNP) antibodies and disease progression underlines the prognostic value of this biomarker. Frequent and standardised nailfold capillaroscopy imaging provided insights into microvascular changes.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• •Patients fulfilling the VEDOSS criteria are at risk of progressing to definite systemic sclerosis (SSc), but the timing and pattern of early progression remains heterogeneous.
• •Nailfold videocapillaroscopy (NVC) abnormalities and SSc-associated autoantibodies are considered important diagnostic modalities for early diagnosis and risk stratification.
• •Data on disease progression in patients with very early SSc and recent-onset puffy fingers are limited.

WHAT THIS STUDY ADDS

• •In this prospective VEDOSS cohort with <3 years of puffy fingers, 43% developed clinically significant disease progression within 3 years.
• •Progression predominantly involved skin and peripheral vascular manifestations, while severe internal organ complications were less frequent in the early phase.
• •Anti-ribonucleoprotein (anti-RNP) antibodies were strongly associated with disease progression.
• •Serial, standardized NVC demonstrated a gradual decline in capillary density and frequent transition from early to active SSc patterns.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• •These findings support close monitoring of patients with very early SSc.
• •Early identification of high-risk patients may facilitate timely intervention and improve stratification in future interventional trials.
• •Longitudinal NVC may serve as a useful tool to monitor microvascular evolution in the earliest disease stages.

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INTRODUCTION

Systemic sclerosis (SSc) is a complex autoimmune disorder characterised by fibrosis and vascular changes affecting the skin and internal organs [1]. Raynaud’s phenomenon (RP) usually precedes the skin involvement by several weeks to several years. Patients who fulfil the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2013 criteria for SSc can be subclassified according to the extent of skin involvement into SSc sine scleroderma, limited cutaneous SSc, or diffuse cutaneous SSc. The concept of early SSc ranges from a long-term pre-scleroderma phase without fibrotic symptoms at risk of developing SSc, to a confirmed diagnosis of SSc with short disease duration. The introduction of the Very Early Diagnosis of Systemic Sclerosis (VEDOSS) criteria marked an important step in more accurately identifying convertors in this early, pre-SSc stage [[2], [3], [4]]. Applying these criteria, however, may result in a heterogeneous group of patients, including both patients with early disease and those with longstanding mild disease [5]. To better identify individuals at risk of disease progression, a time aspect was added to the adjusted VEDOSS criteria—specifically, the presence of puffy fingers for a duration of less than 3 years [3,6].

Timely diagnosis and intervention in SSc might be of value for improving patient outcomes and preventing severe complications, including irreversible organ damage [4]. However, diagnosing the disease in its initial stages may remain a challenge. Also, the transition from very early to progressive SSc, characterised by worsening of fibrosis and organ complications, can vary significantly between patients. Identifying predictive factors of disease progression will help to inform and optimise timely SSc treatment strategies.

The objective of this study was to evaluate the progression from patients meeting the adjusted VEDOSS criteria, to progressive SSc with skin and/or organ involvement. Specifically, we aimed to assess the incidence of progression, and explored several clinical characteristics and biomarkers that predict disease progression. Finally, we set out to describe the course in microvascular changes, analysed through nailfold videocapillaroscopy (NVC). These insights may improve prognostic accuracy, inform timely intervention strategies, and guide personalised treatment approaches, ultimately resulting in better outcomes in the future.

METHODS

Study population and design

We performed a longitudinal, multicentre cohort study with a follow-up period of 3 years. All patients had previously participated in the Hit Hard and Early (HHE) trial [6]. Recruitment for the HHE trial took place between 2017 and 2020 at the Department of Rheumatology of Radboud University Medical Center (Radboudumc) in Nijmegen, The Netherlands and the Department of Rheumatology of the University Hospital Gent in Belgium. The inclusion criteria were as follows: age 18 years or older; presence of RP; positive test for SSc-associated autoantibodies; early or active SSc pattern at NVC; and puffy fingers for less than 3 years. Exclusion criteria were any skin or internal organ involvement, previous immunosuppressive treatment for SSc, and anti-RNA polymerase III autoantibodies. All patients provided written informed consent. Of note, as the primary trial was negative, this cohort was regarded as an untreated cohort.

Assessments within the HHE trial were previously described [6]. For this extension study, patients were evaluated at the outpatient clinic including history, physical examination, laboratory work up, and NVC at 18, 24, 30, and 36 months, respectively. All images of nailfold capillaries were evaluated by 2 trained physicians (MCV and VS). Pulmonary function tests were performed at 24 and 36 months. High-resolution CT was performed in case of relevant pulmonary function decline, defined as a ≥10% decrease in forced vital capacity (FVC) or a decrease in FVC ≥5% to <10% and a diffusing capacity of the lung for carbon monoxide (DLCO) decline of ≥15% [7]. Echocardiography during follow-up was only performed if clinically indicated, eg, signs or symptoms suggesting pulmonary arterial hypertension, or decline in diffusion capacity.

Outcomes

The primary study endpoint was the time to significant disease progression, defined by internal organ involvement as outlined in Table 1 [8,9], or the initiation of immunosuppressive treatment.

Table 1.

Definition of significant disease progression

Study outcome	Description
Skin involvement	Increase in mRSS ≥3 points [8].
Pulmonary involvement	•ILD diagnosed by the presence of ILD on HRCT (pulmonary fibrosis, ground-glass opacities or honeycombing). •PAH confirmed by right heart catheterisation.
(Peripheral) vascular involvement	•Digital ulcer or gangrene. •GAVE diagnosed through gastroscopy.
Heart involvement, n (%)	Peri- or myocarditis on echocardiogram or cardiac MRI if applicable.
Gastrointestinal involvement, n (%)	Occurrence of intestinal obstruction or malabsorption syndrome.
Scleroderma renal crisis, n (%)	Renal crisis defined by the proposed SRC classification [9].
Musculoskeletal involvement, n (%)	•Arthritis. •Myositis as clinical objectified muscle loss (MRC <5/5) and creatine kinase >2 times upper limit of normal.

GAVE, gastric antral vascular ectasia; HRCT, high-resolution computed tomography; ILD, interstitial lung disease; MRC, muscle strength grading; MRI, magnetic resonance imaging; mRSS, modified Rodnan skin score; PAH, pulmonary arterial hypertension; SRC, scleroderma renal crisis.

Statistical analysis

Descriptive statistics are presented as frequencies (percentages) for categorical variables and as means with SDs or medians with IQRs for continuous variables. Kaplan-Meier analyses are performed to evaluate disease progression over time. Cumulative incidence rates of organ involvement during follow-up are provided. Univariate Cox proportional hazards regression is used to assess the impact of clinical risk factors and microvascular changes on disease progression. Descriptive statistics are also employed to analyse changes in NVC patterns and alterations in capillary density over time. All analyses are reported with 95% CIs, no correction for multiple testing was done. Analyses were made in StataNow, version 18.5.

Statement of ethics and consent

Approval for the original HHE trial was given by country-specific medical ethical committees; the commissie mensgebonden onderzoek Arnhem-Nijmegen (Medical Research Ethics Committee [METC] nr 2015-2097) for the Netherlands, and the commissie voor medische Ethiek University hospital Gent (Ethics Committee [EC], UZG 2019/047) for Belgium this is in accordance with Good Clinical Practice and the Declaration of Helsinki.

RESULTS

Thirty patients were included in the study, with the baseline characteristics of the study population summarised in Table 2. The majority of patients were female (70%), with a mean age of 50.1 ± 12.9 years. Of the patients, 26 (87%) presented with puffy fingers as the first non-RP. Since the exact onset of non-RP in the remaining 4 patients was unknown, disease duration—defined as the time from fulfilment of the adjusted VEDOSS criteria—was excluded from this analysis. Anticentromere antibodies were present in 22 (73%) patients. Regarding NVC, all patients had NVC abnormalities, with 21 patients (70%) exhibiting an active scleroderma pattern, and 9 (30%) patients showing an early scleroderma pattern at baseline. All patients were treatment-naïve with regard to immunomodulatory drugs. Concomitant medication use included ACE inhibitors in 2 patients (7%) and anticoagulants in 3 patients (10%) [6].

Table 2.

Baseline characteristics

Characteristics (n = 30)
Age in years, mean (SD)	50.1 (12.9)
Sex
Male, n (%)	9 (30)
Female, n (%)	21 (70)
Current smoker, n (%)	3 (10)
RP duration in months, median (IQR)	26 (9-53)
Puffy fingers duration in months, median (IQR)	5.5 (3-12)
Presence of telangiectasia, n (%)	5 (17)
Presence of calcinosis cutis, n (%)	0 (0)
First non-Raynaud’s phenomenon
Puffy fingers/hands, n (%)	26 (87)
Oesophageal involvement, n (%)	1 (3)
Teleangiectasia, n (%)	2 (7)
Nailfold lesions by vision, n (%)	1 (3)
ESR in mm/h, mean (SD)	11.6 (11.9)
Serum creatinine in mmol/L, mean (SD)	74.2 (15.7)
Antibody profile
Anti-centromere, n (%)	22 (73)
Anti-Scl70, n (%)	4 (13)
Anti-RNP, n (%)	3 (10)
Others,a n (%)	3 (10)
Pulmonary function
FVC% predicted, median (IQR)	105 (95-117)
DLCO% predicted, median (IQR)	88 (81-99)
Nailfold videocapillaroscopy pattern
Early, n (%)	9 (30)
Active, n (%)	21 (70)
Late, n (%)	0 (0)
Capillary density
Normal capillary density,b n (%)	14 (47)
Capillary density, mean (SD)	7.18 (1.49)
Presence of giant capillaries, n (%)	27 (90)
Presence of microhaemorrhages, n (%)	27 (90)

DLCO, diffusing capacity for carbon monoxide; ESR, erythrocyte sedimentation rate; FVC, forced vital capacity; RNP, ribonucleoprotein; RP, Raynaud’s phenomenon; VEDOSS, Very Early Diagnosis of Systemic Sclerosis.

^aOther auto antibodies: anti-Smith antibodies, anti-Sjögren's-syndrome-related antigen A (SSA), and antifibrillarin.

^bCapillary density ≥7/mm.

Incidence and risk of disease progression

Over a 3-year period, 13 patients (43%, 95% CI: 25.6%-61.2%) experienced significant disease progression, which increased to 22 patients (73%, 95% CI: 54.1%-87.7%) when including pitting scars and modified Rodnan skin scores of 1 and 2. Cumulative incidence rates by organ system are presented in Table 3. There was no statistically significant difference in the 3-year incidence between the methylprednisolone group and the placebo group (48% vs 33%, respectively; Fisher’s exact test, P = .69). The progression-free survival analysis for overall significant disease progression is displayed in Figure.

Table 3.

Cumulative incidence of any novel organ involvement during follow-up

Novel organ involvement	3-y incidence
Skin involvement,a n (%)	13 (43%)
Pulmonary involvement
ILD, n (%)	3 (10%)
Pulmonary arterial hypertension, n (%)	1 (3%)
(Peripheral) vascular involvement
Pitting scar, n (%)	7 (23%)
Digital ulcer, n (%)	3 (10%)
Gangreen, n (%)	0 (0%)
Gastric antral vascular ectasia, n (%)	2 (7%)
Heart involvement, n (%)	1 (3%)
Gastrointestinal involvement, n (%)	0 (0%)
Scleroderma renal crisis, n (%)	0 (0%)
Musculoskeletal involvement, n (%)
Arthritis, n (%)	4 (13%)
Myositis, n (%)	0 (0%)

ILD, interstitial lung disease; mRSS, modified Rodnan skin score.

^amRSS score >0.

Figure.

Progression-free survival curve showing overall time to significant disease progression during follow-up, with time expressed in months on the X-axis.

Table 4 presents the results of a univariate Cox regression analysis evaluating risk factors for relevant disease progression. Baseline clinical and NVC variables were assessed, with most showing no statistically significant associations with disease progression (low hazard rates, and P values >.05). However, a potential trend was observed suggesting a reduced risk of disease progression associated with anticentromere antibodies at baseline. Notably, the presence of anti-RNP antibodies was significantly associated with an increased risk of disease progression (hazard ratio [HR] = 32, P = .003). A univariate Cox regression analysis stratified by HHE treatment arm is provided in Supplementary Table.

Table 4.

Univariate Cox regression analysis of baseline risk factors for relevant disease progression

variable	HR	95% CI	P value
Age (per y)	1.03	0.96-1.09	.17
Female sex	1.53	0.42-5.55	.52
Current smoker	0.62	0.08-4.80	.65
RP duration in months	0.98	0.96-1.01	.14
Puffy fingers duration in months	0.99	0.93-1.05	.65
ESR in mm/h	1.03	0.99-1.07	.13
Serum creatinine in mmol/L	1.00	0.97-1.04	.94
Antibody profile
Anticentromere	0.37	0.12-1.14	.09
Anti-Scl70	0.55	0.07-4.37	.58
Anti-RNP	32	3.3-314	.003
Pulmonary function
FVC% predicted	1.03	0.98-1.18	.20
DLCO% predicted	0.98	0.93-1.03	.40
NVC pattern
Early	0.92	0.28-2.98	.89
Active	1.09	0.34-3.55	.89
Capillary density
Mean capillary density (per 1 capillary/mm increase)	0.97	0.65-1.45	.90

DLCO, diffusing capacity for carbon monoxide; ESR, erythrocyte sedimentation rate; FVC, forced vital capacity; HR, hazard ratio; NVC, nailfold videocapillaroscopy; RNP, ribonucleoprotein; RP, Raynaud’s phenomenon.

In Table 5, changes in nailfold capillary microscopy patterns over time are shown. At baseline, the majority of patients (70%) exhibited an active scleroderma pattern. Over the 36-month follow-up period, the mean capillary density gradually decreased from 7.18 (SD = 1.49) at baseline to 6.59 (SD = 1.52) at 36 months (paired t-test, t(22) = 2.06, P = .025). The number of patients showing an active SSc pattern remained relatively stable (64% at 12 months, 76% at 24 months, and 65% at 36 months), while an early SSc pattern decreased over time. Notably, 5 patients (55%, 95% CI: 21.2%-86.3%) with an early SSc pattern at baseline transitioned to an active scleroderma pattern within 24 months. Only 1 patient (5%, 95% CI: 0.1%-23.8%) transitioned from an active SSc pattern to an early SSc pattern.

Table 5.

NVC changes over time

NVC characteristics per timepoint
	Baseline (n = 30)	12 mo (n = 28)	24 mo (n = 25)	36 mo (n = 23)
Capillary density, mean (SD)	7.18 (1.49)	6.82 (1.63)	6.85 (1.30)	6.59 (1.52)
Normal pattern, n (%)	0 (0)	0 (0)	0 (0)	0 (0%)
Nonspecific/not evaluable pattern, n (%)	0 (0)	2 (7)	3 (12)	5 (22)
Early SSc pattern, n (%)	9 (30)	6 (22)	1 (4)	2 (9)
Active SSc pattern, n (%)	21 (70)	18 (64)	19 (76)	15 (65)
Late SSc pattern, n (%)	0 (0)	2 (7)	2 (8)	1 (4)
Conversions from baseline, n (%)
		At 12 mo	At 24 mo	At 36 mo
Early to active/late SSc pattern (n = 9)		1 (11)	4 (44)	0 (0)
Active/late to early SSc pattern (n = 21)		1 (5)	0 (0)	0 (0)

NVC, nailfold videocapillaroscopy; SSc, systemic sclerosis.

DISCUSSION

In this prospective cohort study of patients fulfilling the adjusted VEDOSS criteria, we observed a high cumulative incidence of disease progression over a 3-year follow-up period of 43% up to 73%. Our data are largely comparable to previous reports. The prospective validation study of the VEDOSS criteria showed that 52% of patients meeting the VEDOSS criteria transitioned to fulfil the 2013 ACR/EULAR criteria for SSc after 5 years of follow-up [10]. In addition, among a subset of 695 patients from the European Scleroderma Trial and Research group cohort with a baseline visit within the first year after RP onset, the median time to the first non-RP manifestation was only 0.9 years (IQR: 0-4.2) [11]. Moreover, 90% of these patients developed skin involvement, gastrointestinal symptoms, or a DLCO <80% of predicted within 12 years, often already within the first year.

Our study highlights several important clinical insights. First, skin and peripheral vascular progression were predominant features. Given the uniquely well-defined very early disease stage in our cohort—all with puffy fingers for less than 3 years—these findings underscore the importance of close monitoring for skin and vascular progression. Serious complications affecting the lungs, muscles, or other organs were however relatively rare within the first 3 years, but do occur in this patient group.

Second, longitudinal NVC data revealed a gradual but small decline in mean capillary density over time. While in established SSc baseline scleroderma patterns as well as changes of capillaroscopic characteristics over time are predictive for disease progression, none of the patients in our VEDOSS cohort met the definitions for longitudinal change of capillaroscopic characteristics (ie, 60% reduction of number of capillaries between 2 visits) [12,13]. Hence, the value of longitudinal quantitative NVC changes cannot be evaluated in this VEDOSS cohort. Conceivably, a substantial proportion of patients presenting with an early pattern at baseline progressed to an active pattern. Notably, no patient reverted to a normal pattern during follow-up, underscoring the unidirectional nature of microvascular damage in SSc in an untreated cohort.

Third, anti-RNP antibody positivity emerged as a significant and strong predictor of disease progression, with an HR of 32.5. However, this finding warrants cautious interpretation due to wide CIs due to the low number of anti-RNP-positive individuals. Importantly, there were no clinical signs for mixed connective tissue disease during the 3-year follow-up in these patients. Conversely, trends towards a reduced risk of progression in patients with anticentromere antibodies suggest that this marker may indicate a more indolent disease course in the early stages, though statistical significance was not reached.

Despite the strengths of a prospective follow-up and the availability of high-quality serial NVC assessments, this study has several limitations. First, approximately two-thirds of the patients received intravenous methylprednisolone as part of the HHE trial [6]. However, this intervention did not demonstrate benefit on the primary or any of the secondary endpoints in the original trial and has not been regarded as a disease-modifying drug by the SSc community. Second, the small sample size limits the statistical power to anything other than very strong predictors of disease progression. Third, echocardiography was only performed when clinically indicated, possibly leading to underestimation of asymptomatic cardiac involvement. Because we expanded the clinical criteria for disease progression in this follow-up study of the HHE trial, the initiation of immunosuppressive therapy was not included as separate criterion in our analysis.

In conclusion, this study provides additional prospective data on the evolution of a VEDOSS cohort with <3 years of existence of puffy fingers. The high rate of disease progression underscores the potential importance of timely recognition and monitoring to enable timely intervention. Our findings may help guide the design of future interventional trials aiming at disease interception in SSc.

CRediT authorship contribution statement

Dieneke A Haverkort: Writing – original draft, Methodology, Formal analysis, Conceptualization. Alfons A den Broeder: Writing – review & editing, Supervision, Methodology. Brigit E Kersten: Writing – review & editing, Data curation. Vanessa Smith: Writing – review & editing, Supervision, Methodology. Madelon C Vonk: Writing – review & editing, Supervision, Methodology, Conceptualization.