Clinical algorithms for the diagnosis and prognosis of interstitial lung disease in systemic sclerosis

doi:10.1016/j.semarthrit.2017.03.019

Seminars in Arthritis and Rheumatism

Volume 47, Issue 2, October 2017, Pages 228-234

https://doi.org/10.1016/j.semarthrit.2017.03.019 Get rights and content

Abstract

Introduction

Interstitial lung disease (ILD) is currently the primary cause of death in systemic sclerosis (SSc). Thoracic high-resolution computed tomography (HRCT) is considered the gold standard for diagnosis. Recent studies have proposed several clinical algorithms to predict the diagnosis and prognosis of SSc-ILD.

Objective

To test the clinical algorithms to predict the presence and prognosis of SSc-ILD and to evaluate the association of extent of ILD with mortality in a cohort of SSc patients.

Methods

Retrospective cohort study, including 177 SSc patients assessed by clinical evaluation, laboratory tests, pulmonary function tests, and HRCT. Three clinical algorithms, combining lung auscultation, chest radiography, and percentage predicted forced vital capacity (FVC), were applied for the diagnosis of different extents of ILD on HRCT. Univariate and multivariate Cox proportional models were used to analyze the association of algorithms and the extent of ILD on HRCT with the risk of death using hazard ratios (HR).

Results

The prevalence of ILD on HRCT was 57.1% and 79 patients died (44.6%) in a median follow-up of 11.1 years. For identification of ILD with extent ≥10% and ≥20% on HRCT, all algorithms presented a high sensitivity (>89%) and a very low negative likelihood ratio (<0.16). For prognosis, survival was decreased for all algorithms, especially the algorithm C (HR = 3.47, 95% CI: 1.62–7.42), which identified the presence of ILD based on crackles on lung auscultation, findings on chest X-ray, or FVC <80%. Extensive disease as proposed by Goh et al. (extent of ILD > 20% on HRCT or, in indeterminate cases, FVC < 70%) had a significantly higher risk of death (HR = 3.42, 95% CI: 2.12–5.52). Survival was not different between patients with extent of 10% or 20% of ILD on HRCT, and analysis of 10-year mortality suggested that a threshold of 10% may also have a good predictive value for mortality. However, there is no clear cutoff above which mortality is sharply increased.

Conclusion

Clinical algorithms had a good diagnostic performance for extents of SSc-ILD on HRCT with clinical and prognostic relevance (≥10% and ≥20%), and were also strongly related to mortality. Non-HRCT-based algorithms could be useful when HRCT is not available. This is the first study to replicate the prognostic algorithm proposed by Goh et al. in a developing country.

Introduction

Systemic sclerosis (SSc) is a multisystem autoimmune disease of complex etiopathogeny, characterized by the presence of autoantibodies and interplay between three main components: vascular dysfunction, dysregulation of innate and adaptive immunity, and excessive activation of fibroblasts and related cells, resulting in the development of progressive tissue fibrosis [1], [2], [3]. Interstitial lung disease (ILD) is one of the most frequent visceral manifestations and is, currently, the leading cause of disease-related deaths (35% in the largest study to date) [4], [5], [6]. In early autopsy studies, nearly 100% of patients have parenchymal involvement [7]. As many as 50–90% of patients will have interstitial abnormalities on high-resolution computed tomography (HRCT) [8], [9] and 30–75% will have changes in pulmonary function tests [10]. Currently, HRCT is considered the standard method for the noninvasive diagnosis of SSc-ILD [8], [11]. When analyzed in conjunction with the pulmonary function tests, HRCT defines the staging of disease and assists in determining the appropriate therapeutic approach [12], [13].

Several authors have worked to establish and validate clinical algorithms that can predict the diagnosis and estimate prognosis of SSc-ILD [8], [14], [15]. A Canadian group [14] developed a set of clinical decision rules (combining findings of physical examination, chest radiography, and pulmonary function tests) to identify patients with high probability of ILD on HRCT. Goh et al. developed an algorithm, integrating disease extent on HRCT and spirometry, that had good performance in predicting the risk of death related to ILD in English SSc patients [15], which was also validated in Australian patients [16]. This simple classification system showed significant clinical relevance as a prognostic predictor in SSc-ILD, characterizing a subgroup of patients with extensive pulmonary involvement, higher mortality, and lower progression-free survival [15], [16]. In the concept of personalized medicine, these algorithms may help to stratify patients according to their individual risk of progression of ILD [17]. In this study, we aim to evaluate the performance of these clinical algorithms in a cohort of SSc patients from Southern Brazil.

Section snippets

Patients and study design

A total of 188 consecutive patients with SSc were prospectively evaluated between April 2000 and November 2009. All patients were Brazilian and the great majority inhabitants of the urban area of Porto Alegre, RS. To be included, the patient was required to meet the 1980 American College of Rheumatology (ACR) criteria for SSc [18] or the criteria suggested by LeRoy and Medsger [19] for diagnosis of early forms of SSc. Patients with overlapping syndromes were excluded. However, patients with

Patient characteristics

Out of 188 patients evaluated initially, six were excluded for not meeting inclusion criteria. One patient was excluded after diagnosis of chronic hypersensitivity pneumonia, confirmed by lung biopsy. Of these 181 SSc patients, 4 had no HRCTs, a remaining total of 177 patients followed by a median of 11.1 years (ranging from 17 days to 16.2 years), whose characteristics are described in Table 1.

HRCTs assessment

Of the 177 patients, 57.1% presented ILD on HRCT. Among the patients with ILD, median extent of

Discussion

The importance of ILD as a major cause of morbidity and mortality has been increasingly recognized [30]. In the present study, which followed a cohort of 177 SSc patients for up to 16 years and included 79 deaths, we demonstrated that mortality was strongly associated to diagnosis and severity of ILD.

The prevalence of ILD in our SSc cohort was 57.1%. This estimate is consistent with the literature, despite the wide variability reported for several authors (reaching values as high as 91%) [8],

Conclusions

The diagnosis and severity of ILD were associated with mortality in this cohort of SSc patients of Southern Brazil. Our results in general confirms previous evidence suggesting that an extent around 10–20% may be a reasonable threshold for defining a clinically significant ILD on HRCT, although there is no clear cutoff point above which a steep increase in the risk of death is observed. We also demonstrated that the algorithms proposed of Steele et al. [14] had a good diagnostic performance to

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Prevalence of the limited vs. extensive scleroderma-related interstitial lung disease at the time of diagnosis of SSc-ILD based on Goh et al. criteria. Systematic review and meta-analysis
2024, Revista Clinica Espanola
Goh et al. propusieron en 2008 un algoritmo clasificatorio de SSc-EPID limitada o extensa. La prevalencia de ambos en el momento del diagnóstico de SSc-EPID no se conoce con exactitud.
La revisión se realizó mediante MEDLINE y SCOPUS desde 2008 hasta 2023 y utilizando los términos: «sistémica», «esclerodermia» o «enfermedad pulmonar intersticial» [MesH]. Se utilizó la escala de Newcastle-Ottawa para la evaluación de la calificación de los estudios observacionales y la escala de Jadad para los ensayos clínicos. Se realizó el método inverso ponderado por la varianza.
Se incluyeron inicialmente 27 estudios en la revisión sistemática y metaanálisis (SRMA). De ellos, 17 estudios no tenían datos coincidentes. Comunicaron datos de 2.149 pacientes, 1.369 (81,2%) eran mujeres. La edad media era de 52,4 (DE 6,6) años. El 45,2% de los pacientes presentaban el subtipo difuso y el 54,8% el subtipo limitado o esclerodermia sinusal. El 38,7% de los pacientes presentaban anticuerpos antitopoisomerasa positivos y el 14,2% anticuerpos anticentrómero positivos. El porcentaje medio de capacidad vital forzada al inicio del estudio fue del 80,5% (DE 6,9) y de capacidad de difusión pulmonar para el monóxido de carbono fue del 59,1% (DE 9,6). Doce estudios presentaron datos de extensión de SSc-EPID ajustados por PFR y se incluyeron en el metaanálisis. Los 10 estudios observacionales de cohortes se analizaron por separado. El porcentaje global de afectación limitada se estimó en un 63,5% (IC del 95%: 55,3-73; p < 0,001) utilizando el modelo de efectos aleatorios. La heterogeneidad entre estudios (I2) fue del 9,8% (IC del 95%: 0-68,2%). La afectación pulmonar extensa se estimó en 34,3% (IC del 95%: 26-45,4; p < 0,001). La heterogeneidad entre estudios (I2) fue del 0% (IC del 95%: 0-61,6%) con el modelo de efectos aleatorios.
El porcentaje global de SSc-EPID limitada en el momento del diagnóstico de SSc-EPID se estimó en un 63,5% y extensa en un 34,3%.
Goh et al. proposed in 2008 a classificatory algorithm of limited or extensive SSc-ILD. The prevalence of both at the time of diagnosis of SSc-ILD is not known with exactitude.
The review was undertaken by means of MEDLINE and SCOPUS from 2008 to 2023 and using the terms: “systemic”, “scleroderma” or “interstitial lung disease” [MesH]. The Newcastle-Ottawa Scale was used for the qualifying assessment for observational studies and the Jadad scale for clinical trials. The inverse variance-weighted method was performed.
Twenty-seven studies were initially included in the systematic review and meta-analysis (SRMA). Of these, 17 studies had no overlapping data. They reported data from 2,149 patients, 1,369 (81.2%) were female. The mean age was 52.4 (SD 6.6) years. 45.2% of the patients had the diffuse subtype and 54.8% had the limited or sine scleroderma subtype. A total of 38.7% of the patients showed positive antitopoisomerase antibodies and 14.2% positive anticentromere antibodies. The mean percentage of forced vital capacity at baseline was 80.5% (SD 6.9) and of diffusing capacity of the lungs for carbon monoxide was 59.1% (SD 9.6). Twelve studies presented SSc-ILD extension data adjusted for PFTs and were included in the meta-analysis. The 10 observational cohort studies were analyzed separately. The overall percentage of limited extension was estimated at 63.5% (95%CI 55.3–73; p < 0.001) using the random-effects model. Heterogeneity between studies (I²) was 9.8% (95%CI 0–68.2%) with the random-effects model. Extensive pulmonary involvement was estimated at 34.3% (95%CI 26–45.4; p < 0.001). Heterogeneity between studies (I²) was 0% (95%CI 0–61.6%) with the random-effects model.
The overall percentage of limited SSc-ILD at the time of diagnosis of SSc-ILD was estimated at 63.5% and extensive at 34.3%.
Serum and bronchoalveolar lavage fluid levels of soluble B7H3 in patients with interstitial lung diseases
2023, Respiratory Medicine
The B7 family member B7H3/CD276 was recently reported to be involved in the pathophysiology of idiopathic pulmonary fibrosis (IPF). However, the association of B7H3 with prognosis in patients with fibrosing interstitial lung diseases (ILDs), including IPF, remains unclear. This study was investigated to determine the potential of soluble B7H3 (sB7H3) as a biomarker to predict prognosis in patients with fibrosing ILDs.
Patients with ILDs from various categories who underwent bronchoalveolar lavage (BAL) were included in the study. The relationship between sB7H3 levels in serum or BAL fluid (BALF) and clinical variables at the time of ILD diagnosis was studied retrospectively. All patients who met the fibrosing ILD criteria were followed for 5 years.
We found that coexisting malignancy affected the serum, but not the BALF, sB7H3 levels. There was no significant correlation between serum and BALF levels of sB7H3 in 49 ILD patients without malignancy (11 with sarcoidosis, 5 with drug-induced ILD, 22 with IPF, and 11 with ILD associated with systemic sclerosis). We also found that the BALF levels, but not serum levels, of sB7H3 at the time of ILD diagnosis had independent prognostic potential on 5−year survival in patients with fibrosing ILDs. Of note, patients with a higher level of BALF sB7H3 at diagnosis (≥0.100 ng/mL) showed significantly shorter survival than those with lower levels.
This study suggests that BALF sB7H3 could be a novel prognostic biomarker in a broad range of fibrosing ILD patients.
A Data-experience intelligent model to integrate human judging behavior and statistics for predicting diabetes complications
2022, Alexandria Engineering Journal
Diabetes departments of hospitals provided more and more professional data from each case for data-driven learning. However, experts in hospitals argue that their experience can provide more reliable information than statistical data. This paper presents a Data-Experience intelligent model to predict the possibilities of diabetes complications with the occurrence of abnormal signs. The model merges data and experience mathematically by mixing human judging behavior from traditional Chinese medicine and statistical patient data from western medicine, which is under a particular situation. The probabilities given by the model can value the distributions of each diabetic complication while estimating the posterior when multi-abnormal signs occurred. An implement in a specific case is analyzed based on the statistical data and human judging performance, which shows the effectiveness and rationality of the Data-Experience Intelligent model for predicting diabetic complications proposed in this paper. The results give a more comprehensive prediction by synthesizing subjective information and objective information.
Association Between Immunosuppressive Therapy and Incident Risk of Interstitial Lung Disease in Systemic Sclerosis
2021, Chest
Citation Excerpt :
As a study limitation, only 25% had HRCT-confirmed absence of ILD at study baseline (although the majority had HRCT-confirmed absence of ILD at some time before baseline). Instead, we used a published algorithm with high negative predictive value for clinically relevant ILD.5 In addition, one-half of our study population had more than 8 years of disease duration at baseline.
Outcome measurement instrument selection for lung physiology in systemic sclerosis associated interstitial lung disease: A systematic review using the OMERACT filter 2.1 process
2021, Seminars in Arthritis and Rheumatism
The Outcome Measures in Rheumatology (OMERACT) is a research organization focused on improving health care outcomes for patients with autoimmune and musculoskeletal diseases. The Connective Tissue Disease-Interstitial Lung Disease (CTD-ILD) Working Group on Lung Physiology is a group within OMERACT charged with identifying outcome measures that should be implemented in studies of patients with CTD-ILD. The OMERACT Filter 2.1 is an evidence-based algorithm used to identify outcome measures that are truthful, feasible, and able to discriminate between groups of interest. Our objective was to summate evidence (published literature, key opinion leader input, patient perspectives) that would influence the CTD-ILD Working Group's vote to accept or reject the use of two measures of lung physiology, the forced vital capacity (FVC) and the diffusion capacity of carbon monoxide (DLco) for use in randomized controlled trials (RTCs) and longitudinal observational studies (LOSs) involving patients with systemic sclerosis associated ILD (SSc-ILD).
Patient Research Partners (those afflicted with SSc-ILD) and the CTD-ILD Working Group on Lung Physiology were polled to assess their opinion on the FVC and DLco in terms of feasibility; the CTD-ILD Working Group was also queried on these instruments’ face and content validity. We then conducted a systematic literature review to identify articles in the SSc-ILD population that assessed the following measurement properties of FVC and DLco: (1) construct validity, (2) test-retest reliability, (3) longitudinal construct validity, (4) clinical trial discrimination/sensitivity to detect change in clinical trials, and (5) thresholds of meaning. Results were summarized in a Summary of Measurement Properties (SOMP) table for each instrument. OMERACT CTD-ILD Working Group members discussed and voted on the strength of evidence supporting these two instruments and voted to endorse, provisionally endorse, or not endorse either instrument.
Forty Patient Research Partners reported these two measures are feasible (are not an unnecessary burden or represent an infeasible longitudinal assessment of their disease). A majority of the 18 CTD-ILD Working Group members voted that both the FVC and DLco are feasible and have face and content validity. The systematic literature review returned 1,447 non-duplicated articles, of which 177 met eligibility for full text review. Forty-eight studies (13 RCTs, 35 LOSs) were included in the qualitative analysis. The FVC SOMP table revealed high quality, consistent data with evidence of good performance for all five measurement properties, suggesting requisite published evidence to proceed with endorsement. The DLco SOMP table showed a lack of data to support test-retest reliability and inadequate evidence to support clinical trial discrimination. There was unanimous agreement (15 [100%]) among voting CTD-ILD Working Group members to endorse the FVC as an instrument for lung physiology in RCTs and LOSs in SSc-ILD. Based on currently available evidence, DLco did not meet the OMERACT criteria and is not recommended for use in RCTs to represent lung physiology of SSc-ILD. The OMERACT Technical Advisory Group agreed with these decisions.
The OMERACT Filter 2.1 was successfully applied to the domain of lung physiology in patients with SSc-ILD. The FVC was endorsed for use in RCTs and LOSs based on the Working Group's vote; DLco was not endorsed.
Association between gastroprotective agents and risk of incident interstitial lung disease in systemic sclerosis
2021, Respiratory Medicine
Citation Excerpt :
Absence of ILD at baseline was assessed using chest high-resolution computed tomography (HRCT) or, if unavailable, then by chest X-ray or typical “velcro-like crackles” on physical examination [4]. This published algorithm was created to palliate for the absence of annual HRCT testing in routine practice and has been shown to have high negative predictive value (93.3% and 97.8%) for clinically and prognostically relevant (≥10% and ≥20%) ILD on HRCT [15]. To avoid inclusion of prevalent ILD cases undiagnosed at cohort entry and recorded only at the first follow-up visit, patients needed to be free of ILD for two consecutive visits from cohort entry.
Although interstitial lung disease (ILD) occurs in over half of systemic sclerosis (SSc) patients and represents a leading cause of mortality, there are currently no preventative strategies. We evaluated if gastroprotective agents were associated with a lower incident risk of SSc-ILD.
An SSc cohort without clinically apparent ILD at baseline was constructed from the Canadian Scleroderma Research Group registry. The primary exposure was any use of gastroprotective agents. Treatment with promotility agents was assessed as a secondary exposure. Time to development of clinically apparent ILD was compared between exposed and unexposed person-time, using a multivariable marginal structural Cox model incorporating inverse probability of treatment weights to address time-varying confounding.
In total, 798 subjects met inclusion criteria. At cohort entry, median disease duration was 7.6 (IQR 3.9–15.6) years. During a median 4.4 (IQR 2.6–7.2) years of follow-up, 158 new ILD cases were diagnosed, for a crude incidence of 4.4 (95% CI 3.8–5.1) events per 100 person-years. Most (2085, 73.4%) person-visits were exposed to gastroprotective agents, 579 (20.4%) were exposed to promotility agents, and 554 (19.5%) were exposed to both agents. The marginal structural weighted hazard ratio (HR) for incident ILD related to gastroprotective agents was 0.86 (95% CI 0.52–1.41). When exposure was defined as treatment with promotility agents, the weighted adjusted HR was 0.79 (95% CI: 0.35–1.77).
In this large retrospective cohort study, we were unable to demonstrate a protective role for gastroprotective and promotility agents in preventing clinically apparent SSc-ILD.

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Clinical algorithms for the diagnosis and prognosis of interstitial lung disease in systemic sclerosis

Abstract

Introduction

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Patients and study design

Patient characteristics

HRCTs assessment

Discussion

Conclusions

Rev Bras Reumatol

Semin Arthritis Rheum

Am J Med

Autoimmun Rev

J Clin Epidemiol

Chest

Scleroderma (systemic sclerosis): classification, subsets and pathogenesis

J Rheumatol

Mechanisms and consequences of fibrosis in systemic sclerosis

Nat Clin Pract Rheumatol

Changes in causes of death in systemic sclerosis, 1972–2002

Ann Rheum Dis

Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database

Ann Rheum Dis

Scleroderma lung disease

Eur Respir Rev

Interstitial lung disease in progressive systemic sclerosis: high-resolution CT versus radiography

Radiology

Update on the profile of the EUSTAR cohort: an analysis of the EULAR Scleroderma Trials and Research group database

Ann Rheum Dis

High-resolution computed tomography and scleroderma lung disease

Rheumatology

Interstitial lung disease in systemic sclerosis: where do we stand?

Eur Respir Rev

Interstitial lung disease in connective tissue disease—mechanisms and management

Nat Rev Rheumatol