Abstract
Objective. To address the hypothesis that very early patients with systemic sclerosis (SSc) are a heterogeneous group with mild or early disease, we analyzed the extent of heterogeneity in clinical, epidemiological, and immunological characteristics of these patients.
Methods. We performed an analysis of very early SSc patients from the Zurich cohort, who fulfilled neither the 2013 American College of Rheumatology (ACR)/European League Against Rheumatism nor the 1980 ACR classification criteria, but had a clinical expert diagnosis of SSc with Raynaud phenomenon (RP) and additional features of SSc (puffy fingers, SSc-specific antibodies, SSc pattern on nailfold capillaroscopy, or any organ involvement characteristic for SSc). Disease duration was defined from first RP symptom.
Results. One hundred and two patients fulfilled the inclusion criteria and were analyzed. Their clinical presentation was heterogeneous with the large majority presenting with RP, antinuclear antibodies, and nailfold capillaroscopy changes, but with varying presentations of other features such as SSc-specific antibodies and early signs of organ involvement. While 54.1% (52/96) of patients had a disease duration of < 5 years, as many as 29.1% (28/96) of patients had a disease duration of > 10 years, indicating long-standing mild disease. Patients with very early, potentially progressive disease did not differ from patients with long-standing mild disease in terms of their clinical features at first presentation.
Conclusion. This study showed that patients with very early SSc are a mixture with mild or early disease. This needs to be considered in clinical practice for risk stratification and for the study design of patients considered as early SSc.
Systemic sclerosis (SSc) is a rare, chronic connective tissue disease with clinically heterogeneous manifestations. It has a high morbidity and mortality, which highlights the importance of detecting it at an early stage, where therapeutic interventions can prevent progression of organ damage1,2. However, the very early detection of SSc can be challenging. Although the new 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria have a higher sensitivity than the 1980 ACR classification criteria, there are still patients who do not fulfill the 2013 ACR/EULAR classification criteria but show early signs of SSc3. Analysis of this very early group of SSc patients is of particular interest and high importance for disease management because very early intervention has been shown to profoundly improve disease course and outcome in a variety of different inflammatory rheumatic diseases4,5.
Very early SSc can be characterized by the Very Early Diagnosis of Systemic Sclerosis (VEDOSS) criteria, which includes a varying combination of Raynaud phenomenon (RP), puffy fingers, abnormal nailfold capillaroscopy (NFC) and antinuclear antibodies (ANA)/SSc-specific autoantibodies6,7,8,9. While these VEDOSS patients might represent early stages of SSc progressing into definite clinically established SSc, they also could represent a very mild form of SSc that will not progress to definite SSc. We currently lack validated criteria to differentiate very early, potentially progressive SSc patients from very mild, nonprogressive SSc patients. This is a major limitation for clinical practice, as very mild patients need a very different follow-up, risk stratification, and treatment strategy than potentially progressive patients. Very mild, stable patients should also not be recruited for clinical trials looking at early therapeutic interventions in VEDOSS patients. Thus, the question—whether patients who can be classified as VEDOSS are a mixed group of mild, stable SSc patients and early, progressive SSc patients—greatly affects both clinical practice and clinical trial design.
To address the hypothesis that VEDOSS patients are a heterogeneous group of mild and early patients, we analyzed the extent of heterogeneity in clinical, epidemiological, and immunological characteristics of very early SSc patients from the Zurich cohort.
MATERIALS AND METHODS
Clinical characteristics of the very early SSc patients from the Zurich cohort were analyzed in this study. They were consecutively recruited from the outpatient clinic and fulfilled neither the 2013 ACR/EULAR nor the 1980 ACR classification criteria for SSc, but had shown in addition to RP clinical features of SSc (puffy fingers, SSc-specific antibodies, SSc pattern on NFC or any organ involvement)10,11,12. Patients with primary RP (RP without any of the manifestations above) were excluded. All patients underwent the standard assessments for very early SSc as defined previously7,13. This included assessment by the detection of pulmonary arterial hypertension in SSc (DETECT) score, and patients with an increased score were sent for right heart catheterization14. Demographic and disease characteristics of the patients enrolled between January 2009 and June 2018 were analyzed cross-sectionally. All patients signed an informed consent for enrollment into the Zurich database. The study has been approved by the Cantonal Ethics Committee of Zurich and has been done according to the Declaration of Helsinki.
Disease duration was calculated as the difference between the baseline visit date and the date of the first RP symptom reported by the patient15,16. For further analysis, the cohort was divided into 2 subgroups using a cutoff value of < 5 and ≥ 5 years’ disease duration. Frequency comparisons were made using chi-square test and Fisher exact test for categorical variables, and Mann-Whitney U test for continuous variables. Further, a binary logistic regression was conducted to analyze the association of disease duration and certain clinical features (puffy fingers, digital ulcers, joint contractures, and tendon friction rubs). Data were expressed as frequencies and percentages for categorical variables or as means ± SD and medians ± IQR for continuous variables.
RESULTS
A total of 102 patients met the inclusion and exclusion criteria and were available for analysis in this study. The patients’ demographic and disease characteristics are shown in Table 1. Our data show that several variables were frequently present and thus similar among the very early SSc patients. Altogether 95/99 (96.0%) had ANA, 102/102 (100%) had RP, and NFC was abnormal in 61/79 (77.2%) patients. On the other hand, there was a remarkable heterogeneity in other clinical variables including autoantibodies (anticentromere antibodies 47.5%, anti-RNA polymerase III 5.2%, anti-Scl70 1.0%), puffy fingers (19.0%), telangiectasia (15.3%), gastrointestinal esophageal involvement (28.3%), joint synovitis (12.7%), and interstitial lung disease (5.2%; Table 1). None of the patients showed an increased DETECT score, and therefore, none were sent for right heart catheterization.
If all patients were early progressive patients, then disease duration must have been short, excluding patients with long-standing mild disease. In fact, median disease duration was 4.1 years (IQR 1.6–11.5; Table 1). While around 54% (52/96) of the patients had a disease duration of < 5 years, there was a considerable number of patients with long-standing disease (Figure 1). For example, as many as 29.2% (28/96) patients had a disease duration of > 10 years, virtually excluding them to be classified as early progressive SSc, but rather representing a longstanding, very mild form of SSc.
For clinical stratification, it is important to classify the patients as early, potentially progressive SSc upon their first presentation. Therefore, we wondered if patients with short and longer disease duration were presenting with different clinical characteristics. However, the clinical characteristics of early patients with < 5 and ≥ 5 years’ disease duration showed no statistically significant differences in demographics and disease manifestations even though some clinical features had a higher percentage in patients with disease duration < 5 years such as puffy fingers (22.9% vs 14.0%), joint synovitis (15.4% vs 9.1%), telangiectasia (18.6% vs 13.5%), and DLCO < 70% (10.6% vs 5.0%). Proteinuria and increased C-reactive protein values were also found numerically more frequently in the group with shorter disease duration without reaching statistical significance (Table 2).
In addition, we wanted to assess whether certain clinical variables were independently associated with disease duration as a surrogate for early progressive disease. Clinical variables for logistic regression modeling were chosen based on recent publications and clinical rationale (puffy fingers, digital ulcers as markers of features occurring in patients with early SSc, and joint synovitis and tendon friction rubs being risk factors of disease progression in established SSc)7,17,18,19. However, there was no association of these risk factors and disease duration (data not shown).
DISCUSSION
Even though early detection of SSc is possible, it remains challenging to identify patients at high risk of progression into definite, clinically meaningful SSc. For such progressive patients, very early detection is of key importance for their overall disease outcome, as half of all incident organ manifestations occur simultaneously within 2 years from the first RP5,20. Previous studies also showed that digital ulcers and early internal organ involvement may be already present in VEDOSS patients, which was confirmed by our study20.
However, our study provided an important finding: Patients fulfilling the criteria for very early SSc are a heterogeneous mixture with early disease potentially at risk of progression, and with long-standing, very mild SSc. The current classification of these patients should be reconsidered and needs to be divided into very mild/long-standing and very early, potentially progressive patients. This observation has important implications for the management of patients with very early disease. Patients with mild long-standing disease need different frequencies of follow-up and different considerations for therapeutic interventions than patients with very early disease at risk of progression. Our study also showed that these 2 subgroups of early/mild SSc cannot be easily differentiated based on clinical features on first presentation.
Our study has certain limitations. A limited number of variables was collected by the VEDOSS protocol. Items with > 50% of missing data were excluded from the analysis. The number of patients is rather small, although more than 100 patients were analyzed in our present study. We have taken long-standing disease duration as a measure of mild and stable disease, but it cannot be excluded that patients with very long-standing disease can have disease exacerbation and progression, although this seems rather unlikely from clinical experience. Vice versa, we also cannot exclude that those patients with short disease duration can have mild disease and will never progress. Most importantly, risk factors for progression can only be determined from longitudinal analysis. The VEDOSS study, the largest collection of patients with very mild SSc with a long-term longitudinal follow-up, will be able to address these questions.
In conclusion, our study showed that patients with very early SSc are in fact a mixture of patients with mild and early disease. This needs to be considered in clinical practice and study design of patients with early SSc.
Footnotes
B. Maurer had grant/research support from AbbVie, Protagen, Novartis; congress support from Pfizer, Roche, Actelion, and MSD; and a consultancy relationship with Novartis. In addition, BM has a patent mir-29 for the treatment of systemic sclerosis (SSc) registered. The work of BM is supported by the Prof. Max Cloetta Foundation. O. Distler had a consultancy relationship and/or has received research funding from Actelion, Acceleron Pharma, Amgen, AnaMar, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, Catenion, CSL Behring, Curzion Pharmaceuticals, Ergonex, Glenmark Pharmaceuticals GSK, Inventiva, Italfarmaco, iQvia, Lilly, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Target Bio Science, and UCB in the area of potential treatments of scleroderma and its complications. In addition, Prof. Distler has a patent mir-29 for the treatment of SSc issued (US8247389, EP2331143).
- Accepted for publication March 6, 2020.