Various studies suggest that an impaired DLCO (<80%) may have a predictive value for the development of ILD. Thus, Suliman et al. (49) showed that the DLCO (<80%) was the only frequently pathological parameter in the PFT, compared to FVC or TLC. This in accordance with Showalter et al. (50) demonstrating a sensitivity and specificity of 92.0 and 32.0% for DLCO < 80%, with the highest negative predictive value (NPV) of 63% in patients with SSc. Bernstein et al. (51) reported a sensitivity of 80.0% and specificity of 51.0% with NPV of 68% in detecting ILD by DLCO < 80% in early diffuse SSc. However, TLC shows only sensitivities and specificities intermediate between those of FVC and DLCO (49, 51). Therefore, it can be assumed that TLC is neither suitable for screening nor monitoring of ILD.

In patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), Newall et al. (52) demonstrated no significant differences in FVC, TLC or FEV₁ between patients with or without ILD. Furthermore, the study yielded a reduced DLCO in ANCA vasculitis patients with ILD (52). Rosenberg et al. (53) showed sensitivities of 55% (FEV₁) and 41% (FVC). Therefore, PFT based on FVC, TLC, and FEV₁ alone do not seem not to be valid surrogate parameters for ILD in AAV-patients.

This also applies for patients with myositis, although the study populations are rather small, which makes it difficult to obtain a conclusion. Ideura et al. (54) reported reduced DLCO- and FVC-values and a normal FEV₁ in patients with amyopathic dermatomyositis. The data of a 10-year retrospective analysis published by Chua et al. (55) showed a restrictive ventilatory defect in the majority (79%) of patients with idiopathic inflammatory myositis (IIM) with mean baseline values of FVC and TLC of 70 and 77%, respectively. 94% of patients had a baseline DLCO of <80%. This is in accordance with the results of Won Huh et al. (56), revealing a restrictive defect (92.9%) as the most common PFT abnormality, followed by a low DLCO (88.0%) in patients with polymyositis/dermatomyositis (PM/DM); 80% had a restrictive defect with a reduced DLCO. Fathi et al. (57) observed also restrictive changes on PFT and reduced DLCO in almost all PM/DM-patients with radiological evidence of ILD. Overall, in patients with myositis, restrictive patterns (especially TLC) and a reduced DLCO seem to be important for diagnosing ILD.

As shown in a systematic review by Caron et al. (24), FVC (% predicted) is the most commonly used surrogate marker in studies evaluating ILD progression in SSc-patients. FVC is widely used as primary endpoint in studies, but is also a generally recognized sign of disease progression (decline of 10%) (21, 58, 59). One of the main reasons for FVC’s current popularity in SSc is the fact that FVC is believed to be more specific than DLCO for ILD which can be more useful for monitoring ILD (24). Suliman et al. (49) and Showalter et al. (50) demonstrated a sensitivity and specificity of 37.5–69.0% and 73.0–92.0%, respectively, for FVC < 80%. According to the evidence-based European consensus which has been developed by a panel of 27 European pulmonologists, rheumatologists, and internists with expertise in SSc-ILD, FVC, and DLCO are considered to be useful parameters for evaluation disease progression in SSc (19). In addition, multivariate analyses of a prospective cohort study with SSc-patients identified baseline DLCO as one of the predictors of no fibrosis at follow-up and FVC as predictors of >20% fibrosis at follow-up (60). However, there is still a lack of large ILD studies in IRD, especially for myositis and vasculitis.

Chest X-ray is the most simple and cost-effective method for morphological assessment of the lungs. In everyday clinical practice, it continues to be of value for overview imaging of the lungs or to exclude/confirm infections. However, chest radiographs are insensitive to early changes and may appear normal despite respiratory function test abnormalities and are therefore no longer of any value in diagnosing ILD (67) (see Figure 1).

High-resolution computed tomography is the gold standard for the detection, characterization, and monitoring of ILD (19, 67). According to the Fleischner Society, the term interstitial lung abnormalities (ILA) refers to specific CT findings that are potentially compatible with ILD in patients without clinical suspicion of the disease (66). ILA have been described as non-dependent abnormalities affecting more than 5% of any lung zone (upper, middle, and lower lung zones are demarcated by the levels of the inferior aortic arch and right inferior pulmonary vein) (66). ILA include the following radiological signs (66):

These parenchymal findings can be classified according to the definition by the Fleischner Society and the ATS/ERS (see Tables 3, 4) (67–69) in consideration of the differential diagnosis of idiopathic interstitial pneumonia [e.g., hypersensitivity pneumonia (HP)] according to ATS/ERS (details see Table 5) (67–69). If ILA present less than 5% of any lung zone, they are defined as indeterminate ILA. Depending on the cohort, the prevalence of indeterminate ILD ranges from 32 to 59% (70). According to Putman et al. (70), ILA and indeterminate ILA are associated with a greater all-cause mortality. The transition between ILA and ILD is not clearly defined and should be determined by clinical parameters. Especially in IRD, even small ILA is considered as ILD (66). The diagnostic follow up of patients with indeterminate ILA remains completely unclear, because especially in early cases, no extensive pulmonary changes can be expected, but patients could benefit to a greater extent from therapy.

The most common HRCT-patterns in IRD are NSIP and UIP, depending on the underlying immunologically mediated systemic disorder (28) (see Figures 1, 2A–D, F). According to Goldin et al. (26), among other changes pure ground-glass opacities (pGGO) and PF are the most common HRCT scan findings in patients with symptomatic SSc (see Figure 2E). The extent of PF seen on HRCT scans was significantly negatively correlated with FVC (r = −0.22), DLCO (r = −0.44), and TLC (r = −0.36). A positive correlation was revealed between pGGO and the increased number of acute inflammatory cells found in BAL fluid (r = 0.28). In addition, Remy-Jardin observed that areas of ground-glass attenuation are a reliable indicator of inflammation, as shown in histologic evaluations at open lung biopsy (71). Because differentiation from other causes of GGO such as pulmonary edema, alveolar hemorrhage, NSIP, and hypersensitivity pneumonitis can be challenging, consideration of relevant clinical information such as the chronicity of symptoms, the patient’s immune status, and pre-existing medical conditions is essential (72).

It is difficult to define sensitivity and specificity of HRCT in detecting ILD in IRD-patients. Due to the high resolution, HRCT as a single modality has a very high sensitivity of almost 100% for detecting ILD (27). However, the enhanced image resolution can also result in lower specificity due to unspecific findings. For instance, Hoffmann et al. (27) presented a specificity of 55.3% in detecting ILD in newly diagnosed IRD due to unspecific findings or other diseases. According to the Fleischner Society and Putman et al. (70), the specificity of HRCT may not be 100% and not all changes (ILA and indeterminate ILA) should be considered as being related to ILD. Further invasive diagnostic procedures would be necessary for differentiation.

In conclusion, HRCT is an important diagnostic tool in rheumatology. The evidence-based European consensus statements for identification and management of ILD in SSc recommend that SSc-patients should be screened for ILD using HRCT, particularly if they are showing one or more risk factors (19). In addition, the majority of studies regard HRCT generally as the gold standard for the diagnosis of ILD in IRD (49, 50, 55, 57, 73–75).

Currently, MRI of the lungs is not used in clinical routine for diagnosing ILD, but there were some initial studies showing the potential of MRI in ILD. Although the spatial resolution on MRI is lower than on HRCT, it provides satisfactory results with a sensitivity and specificity of 89 and 91%, respectively, in the detection of ILD in direct comparison, but it can differ based on the technique used (76–78).

In addition, there are studies showing that MRI can differentiate between inflammation- and fibrosis-predominant lesions. Yi et al. (79) correlated biopsies with MRI and demonstrated an early enhancement pattern (82%) on dynamic studies in inflammation-predominant biopsy sites.

Overall, a better assessment and monitoring of ILD in IRD, maybe in combination with HRCT, could be achieved with MRI in the future. Furthermore, there is no risk of exposure to radiation during MRI, which seems to be an advantage for the use of monitoring ILD-IRD and treatment effects.

The addition of PET to CT offers the ability to non-invasively investigate cellular metabolism in vivo and imaging of fine structural details of lung parenchyma (80).

The results of the first study using of ¹⁸F-FDG PET/CT for the investigation of IPF and other diffuse parenchymal lung disease (DPLD) indicate that increased glucose metabolism is associated with both the ground-glass and the reticulation/honeycombing HRCT lung changes (67). In addition, the pulmonary uptake of ¹⁸F-FDG on PET significantly correlated with global health scores and pulmonary physiologic measurements.

Initial data also suggested similar characteristics in IRD. Thus, Bellando-Randone et al. (81) demonstrated in patients with SSc that morphologically “positive” GGO segments showed an increased ¹⁸F-FDG uptake, suggesting the existence of an increased metabolic activity of GGO. According to the authors, these results might indicate that PET/CT may disclose an underlying inflammatory process, which cannot yet be evidenced by HRCT. In addition, Motegi presented similar results in patients with dermatomyositis (82). So far, there are no longitudinal data existing regarding the use of PET/CT in monitoring the course of ILD-IRD. Therefore, further research projects should be initiated to close this knowledge gap and examine the value of this technique in monitoring IRD-patients with known ILD. However, it has to be considered that PET/CT is mainly available in specialized centers and is characterized by high examination costs.

Bronchoalveolar lavage cell patterns and other characteristics can be an useful adjunct in patients with suspected ILD and a lack of confident UIP-pattern on HRCT (83). Although a normal BAL does not exclude ILD, the recognition of a predominantly inflammatory cellular pattern in the BAL can be helpful for the clinician to narrow the differential diagnosis of ILD, and perhaps lessens the need to proceed to more invasive procedures, such as surgical lung biopsy (25, 70–72). In addition, infection and malignancy can be excluded. Furthermore, BAL can be easily and safely performed and the risk of complications is lower than in transbronchial biopsy (84, 85). However, BAL should always be interpreted within the clinical context (medical history, physical examination, and imaging) (83, 86). In patients with suspected ILD, the recommended diagnostic examinations performed on BAL fluid include differential cell count, microbiological studies, and malignant cell cytology laboratory testing (see Table 6) (84, 85). The analysis of the cell patterns in BAL is also called immunological BAL. It has already been shown in the literature that the composition of immunological cells can vary depending on the CT pattern. Ryu et al. (87) reported an elevated lymphocyte count in NSIP compared to UIP in IPF-patients. In addition, differential diagnoses can be evaluated. Domagala described a high total cell count and increased pigmented macrophages in the differential diagnosis of RB-ILD (88). Furthermore, biomarkers measured in BAL could have a value in diagnosing ILD in IRD in the future [e.g., matrix metallopeptidase 9 (MMP-9) or CCL7] (89, 90). However, biomarkers are not yet established in the clinical routine. In Table 6 informative value of different BAL parameters in ILD were summarized.

It should be emphasized that there are no studies or evidence-based recommendations for immunological BAL in diagnosing IRD-ILD available. In addition, protocols for the standardized performance and analysis of a BAL are also lacking which would be essential to compare data. Considering these findings, the diagnostic, prognostic, and therapeutic value of BAL in IRD-ILD remains unclear (91). However, BAL can be a useful tool for the diagnostic evaluation of patients with suspected ILD. In addition, an immunological BAL might be helpful in differentiating between predominantly inflammatory or fibrotic CT patterns in IRD-ILD (23). Further research is necessary to verify these aspects.

In existing ILD in IRD the risk of pulmonary infections (bacteriological, virological, and mycological) is increased with an aggravation due to immunosuppressive therapy (92, 93). Moreover, infection can aggravate clinical symptoms as well as ILD and lead to a delay of the therapy (92, 94). Curtis et al. (94) reported an increased hospitalization rate for RA-ILD patients having a hospitalization for pneumonia in the last 12 months. In this context, BAL can be very helpful for the detection of pulmonary infections and planning an adequate treatment of ILD patients in clinical practice.

Currently, biopsies are performed as open surgery or transbronchial biopsy (cryobiopsy or forceps biopsy) (see Figure 3). In IPF, surgical lung biopsy is still an important tool in a subset of patients who cannot be diagnosed based on clinical and imaging features alone (21, 67). According to the White Paper of the Fleischner Society, biopsy should be considered if the clinical context is indeterminate or the HRCT pattern is not definite or probable UIP (21, 67). As highlighted in the update of the ATS/ERS statement on the international classification of idiopathic interstitial pneumonias (IIP), a multidisciplinary approach does not lessen the importance of lung biopsy in the diagnosis of IIPs; rather, it defines the settings where biopsy is more informative than HRCT and those where biopsy is not needed (59).

There are no clear recommendations concerning the diagnostic value of lung biopsy in patients with IRD-ILD. Only a few publications mention the procedure as an additional option to confirm the diagnosis of ILD in IRD (53, 56). This may also be because patients are often considered to be too old or too sick for biopsy (68). Furthermore, major complications are more frequent in transbronchial biopsy (2.7%) than in BAL (0.12%) and in video-assisted thoracoscopic surgery (VATS) (up to 8%) even higher than in transbronchial biopsy (84, 85, 95). Major complications are especially pneumothorax, hemorrhage, respiratory depression, vasovagal episodes, and bronchospasm. In addition, histological knowledge usually does not change the planned therapy (68). In conclusion, lung biopsy can be helpful to exclude other reasons of ILD in IRD-patients and to achieve a higher diagnostic confidence.

Inflammatory rheumatic disease are characterized by immunological laboratory parameters. Numerous autoantibodies are known and are often used to distinguish between the disease entities (e.g., anti-synthetase syndromes). Several serum autoantibodies associated with ILD are described in the literature. In RA, serum rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (anti-CCP) are associated with ILD (51, 96). Regarding patients with SSc, the presence of anti-topoisomerase I (Scl-70) antibodies is associated with progressive ILD and represent an independent risk factor (19). In myositis, myositis-specific and associated antibodies like anti-melanoma differentiation-associated protein 5 (anti-MDA-5) are an independent risk factor for rapid progressive ILD with high mortality, while anti-aminoacyl tRNA synthetase (anti-ARS) antibodies are associated with subacute ILD (97–99).

By using autoantibodies and other laboratory parameters, predictive models for mortality in IRD-patients with ILD were established. Gono et al. (25) reported a prognostic model in patients with myositis, based on serum levels of C-reactive protein (CRP), KL-6, and MDA-5 status. Similar correlations are known for other IRD.

In addition to the traditional autoantibodies, there are other blood and non-blood biomarkers which a potentially associated with IRD-ILD or have a prognostic factor. These biomarkers are the subject of research, but are not yet part of clinical routine.

In RA, different serum biomarkers (e.g., matrix metalloproteinases) and genetic polymorphisms (e.g., MUC5B) are reported with an association to ILD (100, 101). Furthermore, KL-6 is an experimental biomarker for the presence and progression of ILD in SSc (102, 103). There are also non-blood biomarkers, like the measurement of exhaled alveolar nitric oxide (NO), which correlates with the severity of ILD in SSc (104). In addition, there is evidence that intestinal dysbiosis can lead to increased systemic inflammation and increased extraintestinal involvement (105, 106).

In clinical routine, the diagnosis of IRD-ILD is not made on the basis of a single examination, but is usually based on a combination of different examinations. As described in the literature, the combination of several PFT-parameters did not increase specificity without a significant loss of sensitivity in detecting ILD (49, 50).

Applying a simple clinical decision rule developed by Steele et al. (74) resulted in a sensitivity and specificity of 58.6–88.7% and 60.0%, respectively, in identifying ILD using physical examination or/and chest X-ray. The combination of chest X-ray or PFT (with FVC < 80% and FEV₁/FVC > 70%) achieved a sensitivity and specificity of 60.5% and 77.3% with positive likelihood ratio (LR) 2.67 and negative LR of 0.51, respectively (74). Suliman et al. (49) and Bernstein et al. (51) showed sensitivities and specificities of 59.0–74.1% and 45.7–65.8%, respectively, with positive LR of 1.47–1.7 and negative LR of 0.36–0.6, by using a combination of FVC (<80%) and DLCO (<70 or <80%). According to the results gained by Hoffmann et al. (27), combining chest X-ray and PFT (DLCO < 80%) yielded a sensitivity and specificity of 95.2 and 38.7% with a negative LR of 0.12 in newly diagnosed IRD-patients. By combining (1) PFT (DLCO < 80%) and chest X-ray and (2) HRCT, Hoffmann et al. (27) provided a sensitivity and specificity of 95.2 and 77.4% with a negative LR of 0.06 in newly diagnosed IRD-patients.

So far, there is no established algorithm for screening or monitoring of ILD in IRD available. Especially, studies do not exist yet, which examine the value of clinical examination, non-invasive diagnostics (PFT and imaging), invasive techniques (BAL or biopsy), and biomarkers.

Interpretation of these results would also be challenging, because it is difficult to define a gold standard. Perhaps a diagnosis developed within an ILD board on an interdisciplinary basis should become the gold standard. In the future, an algorithm for screening, monitoring, and prognostic assessment could be developed by combining different techniques (non-invasive, imaging, invasive, and biomarkers).