Skip to main content

The role of lung biopsy for diagnosis and prognosis of interstitial lung disease in systemic sclerosis: a systematic literature review



The prognostic and theragnostic role of histopathological subsets in systemic sclerosis interstitial lung disease (SSc-ILD) have been largely neglected due to the paucity of treatment options and the risks associated with surgical lung biopsy. The novel drugs for the treatment of ILDs and the availability of transbronchial cryobiopsy provide a new clinical scenario making lung biopsy more feasible and a pivotal guide for treatment. The aim of our study was to investigate the usefulness of lung biopsy in SSc ILD with a systematic literature review (SLR).


PubMed, Embase and Cochrane databases were searched up to June 30, 2023. Search terms included both database-specific controlled vocabulary terms and free-text terms relating to lung biopsy and SSc-ILD diagnostic and prognosis. The SLR was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). Studies were selected according to the PEO (population, exposure, and outcomes) framework and Quality assessment of diagnostic accuracy studies (QUADAS) were reported.


We selected 14 articles (comprising 364 SSc-ILD patients). The paucity and heterogeneity of the studies prevented a systematic analysis. Diffuse cutaneous SSc was present in 30–100% of cases. Female predominance was observed in all studies (ranging from 64 to 100%). Mean age ranged from 42 to 64 years. Mean FVC was 73.98 (+/-17.3), mean DLCO was 59.49 (+/-16.1). Anti-Scl70 antibodies positivity was detected in 33% of cases (range: 0-69.6). All patients underwent surgical lung biopsies, and multiple lobes were biopsied in a minority of studies (4/14). Poor HRCT-pathologic correlation was reported with HRCT-NSIP showing histopathologic UIP in up to 1/3 of cases. Limited data suggest that SSc-UIP patients may have a worse prognosis and response to immunosuppressive treatment compared to other histopathologic patterns.


The data from this SLR clearly show the paucity and heterogeneity of the studies reporting lung biopsy in SSc ILD. Moreover, they highlight the need for further research to address whether the lung biopsy can be helpful to refine prognostic prediction and guide therapeutic choices.


Systemic sclerosis (SSc) is a connective tissue disease characterized by microvascular alterations, excessive collagen deposition and autoimmune dysregulation, mainly affecting women (female:male ranging from 3–8:1) with a peak of disease is between 45 and 64 years [1,2,3]. Pulmonary involvement occurs in more than 80% of SSc patients. Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) account for up to 60% of the SSc-associated mortality [4,5,6].

High resolution computed tomography (HRCT) is the imaging gold standard to confirm the presence of ILD in SSc and is considered a sensitive and reproducible method for quantifying the extent of ILD, although radiomics may be more sensitive than visual analysis to capture features indicating SSc-ILD severity on HRCT [7, 8]. However, the radiologic and pathologic correlations between HRCT and lung biopsy features of SSc-ILD remain poorly investigated. The most relevant radiologic pattern observed in SSc-ILD is non-specific interstitial pneumonia (NSIP), but recent studies suggest that among SSc-ILD with late stage disease usual interstitial pneumonia (UIP) is the predominant pattern (87% of cases) and detailed pathologic studies in the early phase of the disease are lacking [9,10,11].

In SSc-ILD patients, lung biopsy is mainly performed when there is a discrepancy between clinical manifestations and HRCT findings and when other diseases, that may complicate SSc clinical course (e.g. lymphomas, lung carcinoma), must be excluded [9]. In selected cases, lung biopsy in combination with BAL may rule out infections, aspiration, and drug toxicity. However, the prognostic role of histopathological subsets and the utility of lung biopsy in guiding the therapeutic strategy in SSc-ILD has been largely neglected [9, 12]. Also the influence of coexistent connective tissue diseases (CTDs) potentially influencing the HRCT and lung biopsy results has also not been properly explored to date. The clinical approach to SSc-ILD contrasts with that of idiopathic interstitial pneumonias (IIPs) where robust data have shown that lung biopsy findings are pivotal in the diagnosis and prediction of prognosis. In fact, histopathological UIP is associated with a worse survival in comparison with other pathological patterns of lung injury [13, 14]. This different diagnostic approach between IIPs and SSc-ILD is due mainly due to: (1) the lack of effective treatment of ILD in SSc, (resulting in the use of clinical features for diagnosis and treatment choices), and (2) the risks and costs associated with the surgical lung biopsy that have discouraged its use in SSc ILD. However, the development of novel drugs for the treatment of UIP/IPF and progressive fibrotic lung disease, and the availability of transbronchial cryobiopsy provide for a new scenario [6, 15]. Moreover, the availability of tissue from cryobiopsy may significantly improve the understanding of SSc-ILD and the consequent management of these patients [9, 15,16,17].

Therefore, we have investigated, through a systematic literature review (SLR) of the available literature, the role of lung biopsy in the management of SSc patients in order to assess its utility either for both clinical practice and research purposes.


Methodology and quality assessment

The SLR was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). Studies were selected according to the PEO (population, exposure, and outcomes) framework outlined in supplementary data S1 (Data S1). Quality assessment of diagnostic accuracy studies (QUADAS) for articles included in the systematic review is summarize in supplementary table S2 (Table S2).

Literature search strategy

PubMed, Embase and Cochrane databases were queried for any relevant publications. Each database was searched from its inception date until June 30th, 2023. Search terms included both database-specific controlled vocabulary terms and free-text terms relating to lung biopsy and SSc-ILD diagnosis and prognosis. Pubmed and Cochrane were interrogated for “biopsy AND (scleroderma OR systemic sclerosis) AND interstitial lung disease AND (diagnosis OR diagnostic OR prognosis OR prognostic)”. Embase was questioned for ' biopsy:ti,ab AND (scleroderma:ti,ab OR ‘systemic sclerosis’:ti,ab) AND ‘interstitial lung disease’:ti,ab AND diagnos*:ti,ab OR (‘biopsy’/exp AND ‘scleroderma’/exp AND ‘interstitial lung disease’/exp AND (‘diagnosis’ OR ‘diagnostic procedure’)).

Eligibility criteria

Articles published in English and addressing lung biopsy in adult patients with SSc-ILD were selected. Study inclusion criteria comprised peer-reviewed publication with population-based studies that reported an association between lung biopsy (all types) and SSc-ILD. Case reports, reviews, congress abstracts, letters to editor and editorials were excluded as well as case series with less than 10 SSc patients. Moreover, studies in which chest CT was not done were excluded. A detailed flow chart describing the study inclusion and exclusion process is available in Fig. 1.

Fig. 1
figure 1

Flow-chart with details on the included and excluded papers

Legend. BAL: Broncho-Alveolar Lavage; ILD: interstitial lung disease; SSc: Systemic Sclerosis

Data extraction

All identified articles were imported into Mendeley for screening. After deduplication, two screening rounds were performed, as described in Fig. 1. Firstly, two reviewers (A.D and F.F) separately evaluated titles and abstracts in terms of relevance for both biopsy and SSc-ILD. In the second round, full texts of the included articles were re-checked for eligibility. In case of disagreement during selection a third reviewer (S.BR) was consulted and a consensus reached.

The extracted contents were as follows: (1) The basic characteristics of the included studies: name of the first author, publication year, location of the studies, study design; study duration (months), total number of included patients, total number of SSc patients in the study, number of control population if present, SSc definition criteria (ACR 2013 criteria, ARA 1980 criteria); (2) other data: percentage of limited and diffuse cutaneous SSc, percentage of female patients, mean age (years), availability of PFTs, FVC (% pred) mean and SD, DLCO (% pred) mean and SD, prevalence of ILDs pattern by CT, biopsy technique (trans-bronchial, cryobiopsy, VATS biopsy, open surgical biopsy), prevalence of ILDs patterns on histopathology, availability and duration of follow up. Any biopsy findings on cellularity, cytokines and molecules expression data, previous or current treatments, autoantibodies, and procedure-related adverse events were also examined.

Statistical analysis

Data for continuous variables are summarized as mean +/- standard deviation (median, minimum and maximum for not normally distributed variables); data for categorical variable are summarized as prevalence, with number and percentages. To compare mortality of UIP-SSc versus NSIP-SSc we pooled the Fisher’s study 5years survival, approximated using Kaplan-Meiers curve, with the Bouros’s study reported 5years survival [18, 19].


Literature search results

The initial search retrieved 933 results from MEDLINE, 473 from Pubmed, 453 from Embase and 7 from Cochrane Collection through June 30, 2023. In Fig. 1, the flow-chart with details on the included and excluded papers are shown. After removal of duplicates, 878 papers were uploaded into Mendeley. First-stage screening by reviewing titles and abstracts excluded 861 publications for not addressing both lung biopsy and SSc-ILD; 17 articles were identified as relevant and assessed for eligibility. After the second-stage screening, 4 articles were excluded because they were not pertinent to the research item. To capture other potentially relevant articles, we also evaluated the full list of references from Reviews, which lead to manual inclusion of 1 additional article which was found to be pertinent to the research item. Finally, 14 articles met all the inclusion criteria constituting the final pool of this SLR (Fig. 1).

Characteristics of the enrolled studies

Characteristics of the included studies are summarized in Table 1. The 14 studies selected in this systematic literature review included 364 SSc-ILD patients. The majority of studies (9/14) were retrospective single center studies. 11 studies based SSc diagnosis on ARA 1980 criteria, whereas two studies used the ACR 2013 diagnostic criteria [20, 21]. In 7 of the included studies, follow up data were available, with a mean duration of 5 years (+/- 4.44).

Table 1 Characteristics of the enrolled studies


Clinical characteristics and lung function

Diffuse cutaneous SSc was variably present in the cohorts, ranging from 30 to 100% of cases. Female predominance was observed in all studies, ranging from 64 to 100%. Mean age in the studies ranged from 42 years to 64 years. Pulmonary function tests (PFTs) were available in all studies except one by Felicio et al. [22] Mean FVC was 73.98 (+/-17.3), mean DLCO was 59.49 (+/-16.1). PFTs value from Yamakawa et al. were not included in the analysis because of lack of separate data for patients with SSc [23].

Autoantibodies pattern

Only 3 studies had ANA data available showing ANA positivity in 96%, 73% and 100% of evaluated patients, respectively, [24,25,26]. Eight studies [19, 22, 23, 27,28,29,30] included data on anti-SCL70 antibodies positivity (median percentage 33%, range 0-69.6), 4 of them also evaluated ACA positivity (median percentage: 6.55%, min 3, max 32.5) [19, 23, 24, 27], and only 3 mentioned anti-RNP positivity (median percentage: 20%, min to (?), max 28) [23, 24, 27].

Previous or current treatments

In the included studies, previous treatment was poorly characterized. All patients in De Carvalho et al. study [31] (N = 18) and 20/25 patients from Xiao et al. [24], were naïve to treatment. The only previous treatments mentioned were corticosteroids (CCS, 5 patients) and cyclophosphamide (CYC, 3 patients). Five out of 14 studies provided information on ongoing treatment at the time of biopsy and the most common drugs used were CYC and CCS [18, 22, 26, 28, 29].

Lung biopsy techniques

Lung biopsies were obtained by surgery in 13 studies: VATS in 6) [18, 23, 25, 26, 28, 31, 32] and open surgical biopsy in 7) [22, 24, 28,29,30, 33, 34]. In one study, endobronchial biopsy was performed to study the bronchial mucosa [27]. None of the studies used transbronchial forceps biopsy or cryobiopsy for lung tissue sampling.

Few studies provided information on guidelines for surgical biopsy. The majority of studies highlighted the importance of avoiding CT honeycombing areas, e one study specified only that two or three biopsy specimens per patient were sampled [31] and in four studies, samples were taken in more than one lobe.28 33 26 None of the studies mentioned adverse events related to the biopsy procedure.

HRCT features

Radiologic findings are summarized in Table 2. CTs or HRCTs were performed in all studies, but in nine radiologic features were not reported. In the remaining five studies HRCT findings were available for 118 patients. NSIP features were reported in 89/118 (75.4%), and UIP in 14/118 (11.9%) patients. Only Yamakawa et al., reported PPFE in 4/72 (5%) cases; the same Authors reported 10/72 cases (13.8%) as unclassifiable ILD by HRCT [19, 22, 23, 26,27,28, 31, 34].

Table 2 SSc-ILD, radiologic and histopathologic features and correlations


Major histopathology findings

Major histopathology findings are summarized in Table 2. In 12 studies, the histopathologic patterns are described, but 4 of them selected only NSIP cases. In the remaining 8 studies (261 LBx) the prevalence of NSIP, detected at the biopsy, was 70.9% (185/261 lung biopsies). The other histopathologic features were UIP in 21/152 cases (13.8%); end stage lung in 7/152 cases (4.6%), centrilobular fibrosis in 15/152 cases (9.8%), RB-ILD in 6/152 (3.9%), and pulmonary hypertension in 2/152 cases (1%) [18, 22,23,24, 26, 27, 30, 33, 34]. Only one study reported 11/32 biopsies as unclassifiable [23].

In 5 studies, NSIP was further classified into cellular or fibrotic (Table 2). Across all studies, fibrotic NSIP was the most prevalent feature in 63.4% (range 16–100%) of cases, while cellular NSIP was less frequently reported: 16.1% (range 0 to 58%).

The presence of CLF (interstitial fibrosis centered on membranous and respiratory bronchioles associated to foreign matter in the lumen due to microaspiration) was assessed in two studies only [28, 35]. Christmann et al. evidenced the presence of CLF in 5/ 21 patients, whereas the other 16 patients presented a NSIP pattern [28]. De Souza et al. showed that CLF was present as an isolated finding in 21% of patients, while some focal regions of this pattern were also found in 84% of patients with predominant NSIP [35].

Radiologic-pathologic correlations

The 4 studies reporting radiologic-pathologic correlations in 73 patients are summarized in Table 2.

Harrison et al. (year of publication 1991) showed that SSc patients without apparent CT changes can have pathologic findings on biopsy: 8 upper or middle lobe biopsies from regions defined as normal by CT were found to have not otherwise specified fibrosis histologically. In 21 cases, CT and histology were concordant in detecting ILDs and 3 normal lungs. In all 3 cases negative both at CT and histology electron microscopy could detect early changes [33].

Three studies (with a total of 46 cases) reported the correlation between HRCT and pathologic patterns: 41 cases showed a NSIP-HRCT pattern, and among them in 36 cases NSIP-HRCT was concordant with histopathology (88%, range 62-100%). Five NSIP-HRCT cases were histologically classified as UIP, (12%) [19, 26, 35]. All UIP-HRCT cases had honeycombing and were confirmed by as UIP on biopsy (4/27 total cases, 15%) [19, 26]. De Souza et al. reported one case of radiological UIP classified as NSIP by pathology [35].

De Souza evaluated HRCT features of patients with CLF and described that centrilobular or airway centered and patchy distribution of the lung involvement were features of CLF patients, while patients with histological NSIP showed peripheral and more diffuse distribution of ground-glass at HRCT: CLF was always associated with coexisting esophageal dilation (> 4 cm diameter) and with a higher frequency of centrilobular nodules (83%) [35].

Cellular findings on histopathology

Biopsy cellularity was examined in a few studies, either on bronchial mucosal biopsies or lung samples. In 23 patients, Sehlstedt et al. evaluated endobronchial biopsies and reported a higher number of neutrophils [27]. In lung biopsies, Harrison et al. evaluated neutrophils, eosinophils, macrophages, lymphocytes, and lymphoid aggregates in o the alveolar spaces and interstitium (determining inflammation): plasma cells were found in the interstitium and lymphoid aggregates and germinal centers were adjacent to bronchioles [33]. In lung biopsies, Yamakawa et al. found plasma cells infiltrate, lymphoid aggregates, germinal centers and fibroblastic foci, both in patients with SSc-ILD and ILD patients with SSc antibodies but without other clinical features of SSc [23].

Molecular findings on histopathology

In 4 studies, data on gene expression, cytokines and other molecular findings in lung or endobronchial biopsies were reported [27]. In mucosal endobronchial biopsies, Sehlstedt et al. found a lower epithelial IL-8 and NFkB expression in SSc-ILD samples compared to controls [27]. Christmann et al. compared gene expression of macrophage markers, chemokines, collagen, as well as transforming growth factor β– and interferon (IFN)–regulated genes, in lung biopsies of SSc-NSIP and controls. They found that expression of these genes correlated with progressive lung fibrosis defined by progression in radiological score (FibMax). Immunohistochemistry confirmed increased markers of collagen (COL1A1), IFN (OAS1 and IFI44), and macrophages (CCL18 and CD163). Moreover, several genes correlated with both the change in FibMax and the change in % predicted forced vital capacity, including IFN and macrophage markers, chemokines, and heat-shock proteins [28]. Parra et al. evaluated different expression of proteins regulating NO synthesis, and found that higher levels of iNOS, IL-13 and bFGF expression in lung biopsies of SSc patients with cellular and fibrotic NSIP correlated with the amount of parenchymal fibrosis [30]. More recently Xiao et al. evaluated 25 lung biopsies in SSc-ILD and found that the hedgehog pathway activation was increased in the lung tissue of SSc-ILD patients and this was decreased by pirfenidone, Sufu (suppressor of fused) was upregulated in lung fibroblasts after pirfenidone challenge, and pirfenidone inhibited the phosphorylation of GSK-3b signalling [24].

Prognostic significance of histopathology features


Among the 14 selected studies, only 4 studies reported SSc-ILD mortality data [18, 19, 23, 29], and only 2 reported the histopathology correlation with survival [18, 19]. Major findings are summarized in Table 3.

Table 3 Prognostic significance of histopathology findings in SSc-ILD

Compared to UIP, NSIP showed better survival rates, but only in the Fisher et al. study did this reach statistical significance (median survival in years 15.3 for NSIP compared to 3 for UIP, p = 0.007) [18, 19]. Pooling the 5 years mortality from the two studies, the difference between histopathologic UIP-SSc and NSIP-SSc didn’t reach statistical significance: overall mortality for UIP-SSc was 37.5% (6/16) compared to 13.8% (9/65), p = 0.06 [18, 19]. Bouros et al. reported no difference in survival for UIP vs. NSIP nor for PFTs trends between fibrotic and cellular NSIP (15 and 47 total cases respectively) [18]. Baseline FVC and DLco, higher BAL eosinophils, DLco deterioration at 3 years and honeycombing at CT significantly correlated with mortality of SSc-ILD [18, 23].

Two prognostic studies compared CTD-ILD to idiopathic NSIP (iNSIP) and there was no mortality difference [22, 31]. Felicio et al. compared 20 iNSIP to 21 CTD-NSIP (10 were SSc-NSIP) confirming the overall good prognosis of NSIP in both groups (overall survival 135 months for iNSIP and 227 months for CTD-NSIP) [22]. De Carvalho et al. compared 22 iNSIP to 18 SSc-NSIP (all fibrotic) finding a higher collagen and elastic fibers content in the SSc-NSIP group, but without prognostic differences on univariate Kaplan Meyer analysis [31].

Disease progression

In 3 studies the functional decline of SSc-ILD was evaluated (Table 3) [18, 26, 35]. Only Kim et al. compared the functional decline between NSIP and UIP, reporting a better outcome after immunosuppressive treatment for NSIP compared to UIP (15% FVC improvement in 5/12 NSIP cases treated with CCS and CYC, compared to no improvement in the 5 UIP patients and a decrease in the CRP score after treatment only in the NSIP group) [26]. Only De Souza compared functional decline between NSIP and CLE without finding any statistically significant difference [35].


This systematic review on the utility of lung biopsy in SSc ILD clearly highlights the need for further research on this topic. Over the last 20 years, only a limited number of studies have employed lung biopsy either in the evaluation and management of patients with SSc-ILD or in order to better understand the pathophysiology of SSc. The present review highlightss the paucity and heterogeneity of the studies in terms of population selection, study aims and data collection. These limitations do not permit a systematic analysis and no solid conclusions on the role of biopsy in SSc-ILD diagnosis and management can be drawn.

Acknowledging those limitations, the most interesting finding of this SLR is that definition of histopathological pattern in SSc-ILD may have a prognostic and therapeutic significance. Only the Fisher study was sufficiently powered to detect a statistically significant difference in mortality among subgroups, providing very low quality evidence that in SSc-ILD UIP pattern may correlate with a higher mortality and a worse response to immunosuppressive treatment compared to NSIP [19, 26]. This finding is well established in IIPs and in rheumatoid arthritis related ILD (RA-ILD) [36]. The PANTHER trial has clearly shown that in UIP/IPF immunosuppression is detrimental and more recently the TRAIL-1 trial has shown that pirfenidone significantly slows lung function decline only in RA-ILD with UIP pattern but not with other patterns [37, 38]. Without further studies these findings cannot be extended to SSc-ILD where UIP pattern may have a different prognostic and theragnostic implications. The Park et al. study was excluded from the present SLR because of the absence of SSc-ILD population data [39]. However, it is important to underline that those Authors found a higher survival rate in CTD-ILD patients compared to IIPs, with CTD-UIP having a better prognosis compared to IPF-UIP, thus suggesting a possible different pathobiological background and prognosis for UIP related to SSc compared to its idiopathic counterpart [39]. In this systematic review, only one study compared the prognosis of cellular and fibrotic NSIP, but it failed to find a meaningful difference [18]. This is strikingly divergent from what is known in IIPs and in other ILDs, where a cellular NSIP has a better prognosis and treatment response compared to fibrotic NSIP [40]. The clinical significance of histopathologic findings in SSc-ILD may also vary over time and among patient subsets. SSc-ILD histopathologic features of the overall population at baseline may differ from those of progressive SSc-ILD. In progressive fibrotic SSc-ILD the prevalence and clinical impact of histopathologic UIP remain completely unexplored. Neither the SENSCIS, nor the INBUILD trial were designed according to histopathology data, therefore the real impact of molecular or morphological histopathological features on treatment response remains unexplored and lung biopsy role for SSc-ILD patients management continues to be neglected [41, 42]. The paucity of data reviewed in this SLR underline the urgent need to explore the universe of SSc-ILD patterns and pathobiological prognostic factors.

In SSc-ILD the UIP-HRCT pattern is rarely found, as it was seen in 13% of cases according to our review. In fact, this SLR confirmed that NSIP-HRCT is be the most prevalent pattern in SSc-related ILD (75%). However, there are limitations to consider. First of all, the majority of the studies predate the 2011 IPF guidelines that defined the diagnostic categories of the fibrotic patterns on HRCT. Moreover, several studies may have had selection bias including a priori only NSIP-SSc, excluding those studies the prevalence of NSIP-HRCT is 61.3%. The studies reviewed in this SLR show that HRCT-pathologic pattern correlation is imprecise. Histological UIP pattern may be present in up to one third of radiological fibrotic NSIP [19].

Among the other histopathologic patterns described in this review, CLF has been explored in 2 studies, with an overall prevalence of 9.8% in SSc-ILD. This pattern seems to correlate with chronic aspiration, a common complication of SSc, and does not seem, with very limited data, to have a meaningful prognostic impact. Given the paucity of studies and the high risk of bias no firm conclusion can be drawn. Moreover, PPFE and unclassifiable ILD, introduced 10 years ago in the histological classification [40], have been reported only in a few studies, and thus remain to be further explored [23]. Radiological PPFE was reported by Enomoto et al. to occur in 19% of patients with CTD-ILD (in 43% of patients with SSc-ILD), and PPFE-like HRCT lesions increased significantly the risk of death for respiratory causes (hazard ratio: 4.10, 95% confidence interval: 1.33–12.65, p = 0.01) [43]. In SSc, Bonifazi et al. have shown the important negative prognostic impact of radiological PPFE, but its biological mechanisms are to be further elucidated [23, 44].

The lung biopsy techniques reported in this SRL are obsolete and therefore we may advocate for future studies relying on more innovative and safer biopsy approaches such as transbronchial cryobiopsy [45]. The number of segments and lobes biopsied is incompletely reported and in many studies only one lobe was biopsied, introducing a risk of potential bias due to discordance of histopathologic features known to occur in different lobes [46]. Future studies should investigate optimal site(s) for lung biopsy using HRCT or more sophisticated guiding systems to allow precise radiologic-pathologic correlations [47]. Cryobiopsy performed in experienced centers for the diagnosis of ILDs is safe [45]. However, the safety data in SSc-ILD are limited. Both the lung function impairment and the possible vascular involvement should be carefully considered in SSc-ILD patients. There are no absolute contraindications to biopsy, but the indication for lung biopsy in patients with pulmonary hypertension or poor lung function should be very carefully balanced against the increased risk of possible severe complications.

Most of the included studies in this SLR were performed before the clinical use of antifibrotic therapies which now provide a much more extensive therapeutic armamentarium: different histopathologic patterns may predict different responses to drugs. In SSc-ILD, Xiao et al. showed the efficacy of pirfenidone as an anti-fibrotic compound in SSc fibrosis-related pathways [24]. In SSc patients, Parra et al. pointed out the importance of selectively inhibit inducible Nytric Oxyde Synthetasis pathway to avoid reperfusion damage during vasodilators treatments, suggesting the need of further study to understand the mechanisms of action of available drugs and to develop new therapies [30]. Novel transcriptomics technique are emerging and the importance of a lung tissue biobank is of critical importance for future development of targeted treatments [48]. There is an urgent unmet need to define histopathological findings in SSc-ILD. Unlike for the idiopathic ILDs, in SSc the real prevalence and significance of NSIP and UIP histopathological patterns remain largely unclear. Understanding whether these morphological patterns have therapeutic or prognostic significance is of major importance. molecular characterization of diseased lung may become part of the future landscape of precision treatment and may supercede morphologic classification and the UIP/NSIP dichotomy. In either case cryobiopsy remains a relatively safe biopsy alternative for traditional histopathologic evaluation and for tissue procurement for molecular studies.

In conclusion, the data obtained from this SLR suggest that lung biopsy does provide discriminating data characterizing pulmonary involvement in SSc patients. Future studies are needed to address whether it can be helpful to either refine our prognostic prediction or to guide treatment.

Data availability

Dataset is available through request to the corresponding author.


  1. Orlandi M, Lepri G, Damiani A, et al. One year in review 2020: systemic sclerosis. Clin Exp Rheumatol. 2020;38(Suppl 125):3–17.

    PubMed  Google Scholar 

  2. Chifflot H, Fautrel B, Sordet C, Chatelus E, Sibilia J. Incidence and prevalence of systemic sclerosis: a systematic literature review. Semin Arthritis Rheum. 2008;37:223–35.

    Article  PubMed  Google Scholar 

  3. Denton CP, Khanna D. Systemic sclerosis. Lancet. 2017;390:1685–99.

    Article  PubMed  Google Scholar 

  4. Tyndall AJ, Bannert B, Vonk M, et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR scleroderma trials and research (EUSTAR) database. Ann Rheum Dis. 2010;69:1809–15.

    Article  PubMed  Google Scholar 

  5. Perelas A, Silver RM, Arrossi AV, Highland KB. Systemic sclerosis-associated interstitial lung disease. Lancet Respir Med. 2020;8:304–20.

    Article  CAS  PubMed  Google Scholar 

  6. Volkmann ER. Natural history of systemic sclerosis-related interstitial lung disease: how to identify a progressive fibrosing phenotype. J Scleroderma Relat Disord. 2020;5:31–40.

    Article  PubMed  Google Scholar 

  7. Wells AU, Hansell DM, Rubens MB, et al. Fibrosing alveolitis in systemic sclerosis: indices of lung function in relation to extent of disease on computed tomography. Arthritis Rheum. 1997;40:1229–36.

    CAS  PubMed  Google Scholar 

  8. Martini K, Baessler B, Bogowicz M, et al. Applicability of radiomics in interstitial lung disease associated with systemic sclerosis: proof of concept. Eur Radiol. 2021;31:1987–98.

    Article  CAS  PubMed  Google Scholar 

  9. Tomassetti S, Colby TV, Wells AU, Poletti V, Costabel U, Matucci-Cerinic M. Bronchoalveolar lavage and lung biopsy in connective tissue diseases, to do or not to do? Ther Adv Musculoskelet Dis. 2021;13:1759720X211059605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Valenzi E, Cody B, Lafyatis R. Usual interstitial pneumonia is the predominant histopathology in patients with systemic sclerosis receiving a lung transplant. Clin Exp Rheumatol. 2023;41:1670–8.

    PubMed  PubMed Central  Google Scholar 

  11. Antoniou KM, Margaritopoulos G, Economidou F, Siafakas NM. Pivotal clinical dilemmas in collagen vascular diseases associated with interstitial lung involvement. Eur Respir J. 2009;33:882–96.

    Article  CAS  PubMed  Google Scholar 

  12. Tomassetti S, Ravaglia C, Puglisi S, et al. Impact of lung biopsy information on treatment strategy of patients with interstitial lung diseases. Ann Am Thorac Soc. 2022;19:737–45.

    Article  PubMed  Google Scholar 

  13. Bjoraker JA, Ryu JH, Edwin MK, et al. Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1998;157:199–203.

    Article  CAS  PubMed  Google Scholar 

  14. Tomassetti S, Ravaglia C, Wells AU, et al. Prognostic value of transbronchial lung cryobiopsy for the multidisciplinary diagnosis of idiopathic pulmonary fibrosis: a retrospective validation study. Lancet Respir Med. 2020;8:786–94.

    Article  PubMed  Google Scholar 

  15. Kuwana M, Distler O. Recent progress and missing gaps to achieve goal in the care of systemic sclerosis-associated interstitial lung disease. J Scleroderma Relat Disord. 2020;5:3–5.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Tomassetti S, Maldonado F, Poletti VCOUNTERPOINT. Should surgical lung biopsy still be performed for interstitial lung disease evaluation? No Chest. 2021;160:2011–4.

    Article  PubMed  Google Scholar 

  17. Nihtyanova SI, Denton CP. Pathogenesis of systemic sclerosis associated interstitial lung disease. J Scleroderma Relat Disord. 2020;5:6–16.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Bouros D, Wells AU, Nicholson AG, et al. Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome. Am J Respir Crit Care Med. 2002;165:1581–6.

    Article  PubMed  Google Scholar 

  19. Fischer A, Swigris JJ, Groshong SD, et al. Clinically significant interstitial lung disease in limited scleroderma: histopathology, clinical features, and survival. Chest. 2008;134:601–5.

    Article  PubMed  Google Scholar 

  20. n den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against rheumatism collaborative initiative. Arthritis Rheum. 2013;65:2737–47.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American rheumatism association diagnostic and therapeutic criteria committee. Arthritis Rheum. 1980;23:581–90.

    Google Scholar 

  22. Felicio CH, Parra ER, Capelozzi VL. Idiopathic and collagen vascular disease nonspecific interstitial pneumonia: clinical significance of remodeling process. Lung. 2007;185:39–46.

    Article  CAS  PubMed  Google Scholar 

  23. Yamakawa H, Hagiwara E, Kitamura H, et al. Clinical features of idiopathic interstitial pneumonia with systemic sclerosis-related autoantibody in comparison with interstitial pneumonia with systemic sclerosis. PLoS ONE. 2016;11:e0161908.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Xiao H, Zhang GF, Liao XP, et al. Anti-fibrotic effects of pirfenidone by interference with the hedgehog signalling pathway in patients with systemic sclerosis-associated interstitial lung disease. Int J Rheum Dis. 2018;21:477–86.

    Article  CAS  PubMed  Google Scholar 

  25. Franco de Carvalho E, Parra ER, de Souza R, Muxfeldt A, Saber A, Capelozzi VL. Parenchymal and vascular interactions in the pathogenesis of nonspecific interstitial pneumonia in systemic sclerosis and idiopathic interstitial pneumonia. Respiration. 2008;76:146–53.

    Article  PubMed  Google Scholar 

  26. Kim DS, Yoo B, Lee JS, et al. The major histopathologic pattern of pulmonary fibrosis in scleroderma is nonspecific interstitial pneumonia. Sarcoidosis Vasc Diffuse Lung Dis. 2002;19:121–7.

    PubMed  Google Scholar 

  27. Sehlstedt M, Andersen GN, Nilsson K, et al. Suppressed signal transduction in the bronchial epithelium of patients with systemic sclerosis. Respir Med. 2009;103:301–8.

    Article  PubMed  Google Scholar 

  28. Christmann RB, Sampaio-Barros P, Stifano G, et al. Association of interferon- and transforming growth factor beta-regulated genes and macrophage activation with systemic sclerosis-related progressive lung fibrosis. Arthritis Rheumatol. 2014;66:714–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Domiciano DS, Bonfa E, Borges CT, et al. A long-term prospective randomized controlled study of non-specific interstitial pneumonia (NSIP) treatment in scleroderma. Clin Rheumatol. 2011;30:223–9.

    Article  PubMed  Google Scholar 

  30. Parra ER, Aguiar Junior AC, Silva LO, Souza HS, Espinoza JD, Capelozzi VL. Morphometric evaluation of nitric oxide synthase isoforms and their cytokine regulators predict pulmonary dysfunction and survival in systemic sclerosis. Braz J Med Biol Res. 2013;46:881–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. de Carvalho EF, Parra ER, de Souza R, A’B Saber AM, Machado Jde C, Capelozzi VL. Arterial and interstitial remodelling processes in non-specific interstitial pneumonia: systemic sclerosis versus idiopathic. Histopathology. 2008;53:195–204.

    Article  PubMed  Google Scholar 

  32. Fisher K. Assessing clinically meaningful change following a programme for managing chronic pain. Clin Rehabil. 2008;22:252–9.

    Article  PubMed  Google Scholar 

  33. Harrison NK, Myers AR, Corrin B, et al. Structural features of interstitial lung disease in systemic sclerosis. Am Rev Respir Dis. 1991;144:706–13.

    Article  CAS  PubMed  Google Scholar 

  34. de Carvalho ME, Kairalla RA, Capelozzi VL, Deheinzelin D, do Nascimento Saldiva PH, de Carvalho CR. Centrilobular fibrosis: a novel histological pattern of idiopathic interstitial pneumonia. Pathol Res Pract. 2002;198:577–83.

    Article  PubMed  Google Scholar 

  35. de Souza RB, Borges CT, Capelozzi VL, et al. Centrilobular fibrosis: an underrecognized pattern in systemic sclerosis. Respiration. 2009;77:389–97.

    Article  PubMed  Google Scholar 

  36. Renzoni EA, Poletti V, Mackintosh JA. Disease pathology in fibrotic interstitial lung disease: is it all about usual interstitial pneumonia? Lancet. 2021;398:1437–49.

    Article  CAS  PubMed  Google Scholar 

  37. Idiopathic Pulmonary Fibrosis Clinical Research N, Raghu G, Anstrom KJ, King TE Jr., Lasky JA, Martinez FJ. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366:1968–77.

    Article  Google Scholar 

  38. Solomon JJ, Danoff SK, Woodhead FA, et al. Safety, tolerability, and efficacy of pirfenidone in patients with rheumatoid arthritis-associated interstitial lung disease: a randomised, double-blind, placebo-controlled, phase 2 study. Lancet Respir Med. 2023;11:87–96.

    Article  CAS  PubMed  Google Scholar 

  39. Park JH, Kim DS, Park IN, et al. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med. 2007;175:705–11.

    Article  PubMed  Google Scholar 

  40. Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188:733–48.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Distler O, Highland KB, Gahlemann M, et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med. 2019;380:2518–28.

    Article  CAS  PubMed  Google Scholar 

  42. Flaherty KR, Wells AU, Cottin V, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med. 2019;381:1718–27.

    Article  CAS  PubMed  Google Scholar 

  43. Enomoto Y, Nakamura Y, Colby TV, et al. Radiologic pleuroparenchymal fibroelastosis-like lesion in connective tissue disease-related interstitial lung disease. PLoS ONE. 2017;12:e0180283.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Bonifazi M, Sverzellati N, Negri E et al. Pleuroparenchymal fibroelastosis in systemic sclerosis: prevalence and prognostic impact. Eur Respir J. 2020;56.

  45. Korevaar DA, Colella S, Fally M et al. European respiratory society guidelines on transbronchial lung cryobiopsy in the diagnosis of interstitial lung diseases. Eur Respir J. 2022;60.

  46. Flaherty KR, Travis WD, Colby TV, et al. Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med. 2001;164:1722–7.

    Article  CAS  PubMed  Google Scholar 

  47. Kronborg-White S, Bendstrup E, Gori L, et al. A pilot study on the use of the super dimension navigation system for optimal cryobiopsy location in interstitial lung disease diagnostics. Pulmonology. 2023;29:119–23.

    Article  CAS  PubMed  Google Scholar 

  48. Vukmirovic M, Kaminski N. Impact of transcriptomics on our understanding of pulmonary fibrosis. Front Med (Lausanne). 2018;5:87.

    Article  PubMed  Google Scholar 

Download references


This study didn’t receive funding.

Author information

Authors and Affiliations



M.M.C. designed the study with the participation of all authors. A.D., F.F. and S.B.R. collected the data. L.T. performed the statistical analysis. All authors revised the data. A.D., S.B.R, S.T. and M.M.C wrote the drafts of the main manuscript text, that was revised by all authors. A.D. and S.T. prepared figures and Tables that were revised by all authors. G.B., G.L., A.M.P., V.P. revised the manuscript. TVC revised the manuscript for content and edited the manuscript for English grammar.

Corresponding author

Correspondence to Sara Tomassetti.

Ethics declarations

Ethics approval

Not applicable.

Competing interests

All authors declare no other competing interests except for MMC who declares speaker’s fee from Boehringer Ingelheim, Biogen, MSD, Lilly and research grants from Boeheringer Ingelheim, MSD and Argenx. S.T. who declares speaker’s fee from Boehringer-Ingelheim, Roche, Erbe, PulmoniX; C.R. and V.P. declare speaker’s fees and advisory board compensations from Boehringer-Ingelheim and Roche. V.P. declares also speaker’s fee from ERBE and AMBU.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1:

Supplementary data S1

Supplementary Material 2:

Supplementary Table S2

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Damiani, A., Orlandi, M., Bruni, C. et al. The role of lung biopsy for diagnosis and prognosis of interstitial lung disease in systemic sclerosis: a systematic literature review. Respir Res 25, 138 (2024).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: