Pulmonary Involvement in Autoimmune-Mediated Disease

Background: Pulmonary involvement in the form of interstitial lung disease (ILD) is an important organ manifestation of many autoimmune diseases (AID). The management of ILD in different types of AID is described.

Methods: This review is based on pertinent publications retrieved by a search in PubMed, with particular emphasis on meta-analyses and randomized controlled trials, supplemented by guidelines, expert consensus statements, and the authors’ clinical experience.

Results: The prevalence of ILD among patients with inflammatory rheumatic systemic diseases ranges from 7% to 50% (7–15% in rheumatoid arthritis, 44–50% in systemic sclerosis, and 33–50% in idiopathic inflammatory myopathies). ILD is much less common in organ-specific types of AID (e.g., multiple sclerosis). ILD takes a progressive, fibrosing course in 16–40% of cases. If the patient’s history or clinical manifestations suggest the possibility of ILD, pulmonary function tests and thin-slice computed tomography of the lung (high-resolution computed tomography, HRCT) should be performed. Patients with types of AID associated with a high prevalence of ILD should undergo regular pulmonary function testing in addition to directed history-taking and lung auscultation. Pulmonary HRCT should be performed on initial diagnosis of an AID. Invasive measures are needed only to resolve differential diagnostic uncertainty. The pharmacotherapy of ILD is initially oriented toward the immune-modulating or immunosuppressive treatment of the underlying disease. Antifibrotic treatment is given in addition in cases of progressive pulmonary fibrosis. The management of ILD should ideally be decided on by an interdisciplinary ILD board. The prognosis of ILD depends on that of the underlying disease; ILD is associated with elevated mortality.

Conclusion: ILDs are critical manifestations of a variety of systemic autoimmune and inflammatory rheumatic diseases. Early recognition and targeted pharmacotherapy optimize the clinical outcome.

Cite this as:: Hoffmann T, Aringer M, Koschel D, Krause A, Wolf G, Pfeil A: Pulmonary involvement in autoimmune-mediated disease. Dtsch Arztebl Int 2025; 122: 669–75. DOI: 10.3238/arztebl.m2025.0162

Systemic autoimmune diseases (AID) and other immune-mediated disorders can involve a number of organs, with the lungs being affected in various ways. Pulmonary involvement in AID in its broader sense includes pleural disorders, airway involvement, such as bronchiectasis and bronchiolitis, pulmonary vascular diseases associated with pulmonary hypertension or alveolar hemorrhage, and parenchymal lung diseases, including interstitial lung diseases (ILDs) (e1). ILD is a key manifestation of lung involvement and may exhibit a range of computed tomography and histomorphological patterns of varying severity (1, 2, 3). Depending on the underlying condition, ILD presents with a progressive, irreversible, fibrotic course in 15 to 40% of cases and is associated with high morbidity and mortality rates (see “Prognosis” section for details) (e2, e3, e4). Prevalence and clinical forms of ILD vary significantly across clinical entities and therefore require risk-adjusted screening and tailored therapy. Thin-slice spiral computed tomography of the lungs (high-resolution computed tomography, HRCT) is the key diagnostic modality. However, it is not always possible to easily identify the underlying disease from CT-morphologic findings; this will often require interdisciplinary assessment (see the “Diagnostics” section for details) (1).

This review aims to present the current state of knowledge of screening, diagnostics, monitoring, and therapy of ILD associated with AID.

Methods

This narrative review is based on pertinent publications retrieved by a search in PubMed (see eTable 1 for search criteria) and the authors’ clinical experience. It includes meta-analyses and randomized controlled trials (RCTs) from the years 2005 to 2024, supplemented by guidelines and expert consensus statements.

eTable 1

Summary of the literature review on interstitial lung disease in autoimmune-mediated diseases

Prevalence

The prevalence of ILD varies significantly between the individual AIDs. Thus, 44 to 50% of patients with systemic sclerosis (SSc) and 33 to 50% of patients with certain clinical subtypes of idiopathic inflammatory myopathy (IIM) present with ILD (4). In all, 67% of patients with SSc-ILD experience progression over a period of five years (5). ILD is less common in other forms of AID; thus, for example, 3 to 10% of patients with systemic lupus erythematosus, 7 to 15% of individuals with rheumatoid arthritis (RA), 12 to 21% of those with primary Sjögren’s syndrome (pSS) (4), and 2 to 25% of patients with anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis have ILD (e5) (Table 1). More information on the prevalence of ILD in spondylarthritis, inflammatory bowel disease, and other immune-mediated diseases may be found in eBox 1. If ILD develops in the setting of AID, it will significantly affect the patient’s prognosis (see the “Prognosis” section for details) (6).

Table 1

Prevalence, autoantibodies, and high-resolution computed tomography patterns in interstitial lung disease in autoimmune-mediated diseases and prevalence of idiopathic pulmonary fibrosis

eBox 1

Prevalence of interstitial lung disease in patients with spondylarthritis, inflammatory bowel disease, and other immune-mediated disorders

Clinical presentation

The clinical symptoms of patients with ILD are nonspecific. They complain of dyspnea, initially only on exertion, and of a usually dry cough (1). More specific, however, is the detection of inspiratory velcro crackles (sclerophony) on auscultation as a clinical indicator of fibrotic lung disease. (7, e6). However, particularly in AID, it has been shown that 31.7% of patients newly diagnosed with ILD present with no pulmonary symptoms at all (e6). Based on this prevalence, structured pulmonary screening of these patients is therefore recommended.

Depending on the underlying disease, certain risk factors are known to be associated with both the incidence and the prognosis of ILD (Figure, eBox 2).

eBox 2

Additional information on the risk factors of interstitial lung disease

Figure

Overview of ILD screening and ILD diagnostic tests for autoimmune-mediated diseases

Diagnostics

The diagnosis of ILD is usually based on a combination of clinical symptoms, lung function tests, and HRCT, along with invasive investigations such as bronchoscopy with bronchoalveolar lavage (BAL) and lung biopsy as needed. Given the heterogeneity of the findings across the various ILD entities, an interdisciplinary discussion of the results at an ILD board is always recommended before establishing a final diagnosis (1) (Figure). The ILD board should include specialists for pneumology, (chest) radiology, (chest) pathology, and rheumatology (1) (eBox 3).

eBox 3

Diagnostic certainty of interstitial lung disease (ILD) through ILD board evaluation

Each patient must be assessed for possible ILD by their medical history (pulmonary symptoms, such as chronic cough, dyspnea, expectoration) and clinical examination (early signs: velcro crackles, late signs: finger clubbing, cyanosis, signs of right ventricular strain) in order to establish the diagnosis of AID and, in the case of positive findings, referred on for targeted ILD diagnostic testing (Figure). Diagnostic investigations for ILD should include lung function tests and chest HRCT (1, 8). On the other hand, in the presence of autoantibodies associated with a high risk of ILD (anti-Scl-70, anti-synthetase antibodies, Ku antibodies, MDA-5 antibodies), ILD diagnostics along the lines of ILD screening should be conducted at initial diagnosis, even if the history reveals no specific signs or clinical findings of ILD (eTable 2) (8).

eTable 2

Risk factors for developing interstitial lung disease secondary to inflammatory rheumatic disorders, according to ACR/CHEST recommendations 2023 (8). The absence of these disease features, however, does not exclude interstitial lung disease; a decision-making process with the patient is required.

The purpose of lung function tests is initially to assess the functional impact of the disease and the effectiveness of drug therapy. They also help identify a progressive fibrotic disease course and assess prognosis; they can also provide differential diagnostic clues of pulmonary involvement when the HRCT scan is unremarkable. Lung function tests should include blood gas analysis, spirometry, body plethysmography, and measurement of diffusing capacity for carbon monoxide (DLCO, ideally corrected for hemoglobin) (1, 8). Spirometry and body plethysmography provide crucial parameters, together with forced vital capacity (FVC) and total lung capacity, for detecting restrictive ventilatory impairment and assessing prognosis (9, e7). On the other hand, reduced DLCO (<80 % of the reference) reflects sensitivities between 80 and 94% for the detection of ILD, so that this parameter plays a vital role as a screening parameter, especially during initial diagnostics or in the early stage of ILD (e6, e8). An HRCT scan should therefore be obtained even in pulmonary asymptomatic AID patients with reduced DLCO (<80%) to exclude ILD (e6). Moreover, reduced DLCO may be an indication of pulmonary arterial hypertension, which can also occur in SSc and many other connective tissue diseases. At the same time, however, it should be noted that, ultimately, normal lung function results do not entirely exclude ILD, so that an HRCT should also be obtained where there is clinical evidence of ILD in the patient’s history and after considering ILD risk factors (eTable 2) (8, e6). More extensive lung function tests include blood gas analysis at rest and on exertion, for example, during a six-minute walk test, in addition to ergooxymetry and cardiopulmonary exercise testing.

Given their low sensitivity (64.2%) and specificity (73.6%), conventional chest X-rays should not be used as the sole diagnostic imaging modality for ILD screening (1, e6). Current guidelines recommend obtaining a chest HRCT for suspected ILD. If this does not demonstrate the typical signs of ILD, then further diagnostic assessment is not required at present, even though ILD may develop over the further course. A few centers use lung ultrasound as part of ILD screening; however, it is still too early to draw conclusions about its diagnostic value (e9).

Given that ILD can precede the initial diagnosis of an AID by several years, antibody tests are recommended at the time of initial ILD diagnosis, even in the absence of an AID diagnosis (Figure) (1). Thus, 9% of patients assumed to have idiopathic pulmonary fibrosis (IPF) developed an AID-ILD during the follow-up period of 6.4 ± 4.9 years, and even 17% of patients with idiopathic nonspecific interstitial pneumonia (NSIP) within 5.5 ± 5.0 years (e10, e11).

Apart from blood sedimentation rate, C-reactive protein, and creatine kinase, an antinuclear antibody (ANA) test and, on confirmation of ANAs, testing for antibodies against extractable nuclear antigens (ENAs) and IgM rheumatoid factors, and anti-citrullinated protein antibodies (ACPA) are also recommended. Obtaining a myositis panel to test for myositis-specific and myositis-associated antibodies should be considered on an individual basis. If the UIP pattern (usual interstitial pneumonia) is radiologically likely or definite, then the additional assessment of myeloperoxidase (MPO)-specific ANCA is also recommended (1).

The nomenclature and classification concept of “interstitial pneumonia with autoimmune features” (IPAF) is discussed in greater detail in the guidelines of the European Respiratory Society (ERS) and the American Thoracic Society (ATS). This includes patients with an ILD in whom autoantibodies have been identified and who present with clinical signs of AID, yet do not fulfill the criteria of a specific AID (10).

The clinical and laboratory tests should include at least the basic examinations listed in the Figure (1) but should be expanded depending on the suspected diagnosis.

eFigure

Typical imaging patterns of interstitial lung diseases (ILD) in autoimmune-mediated diseases

Confirmation of diagnosis

HRCT is the gold standard for detecting, characterizing, and monitoring ILD (1, 8, 11). The best possible assessment of the lung parenchyma is obtained without contrast medium during the HRCT scan (1). Characterization of the morphological findings of HRCT is performed along the lines of the ATS/ERS definition (2, 12, 13). Further information on HRCT patterns is available in eBox 4. At the same time, it should be noted that the HRCT pattern does not usually allow any exact conclusions to be drawn about the underlying disorder.

eBox 4

HRCT patterns of interstitial lung disease (ILD) associated with autoimmune disease

On completion of basic diagnostics (Figure), the patient should be referred to an interdisciplinary ILD board (1). If, after assessing the patient’s history, clinical and laboratory test results, lung function tests, and HRCT findings, no specific AID-ILD diagnosis can be made or other differential diagnoses are being considered, then invasive diagnostic procedures are usually indicated (1). BAL and lung biopsy (nowadays, usually in the form of cryobiopsy, but also as an open surgical procedure) are particularly worth mentioning in this context (eBox5). If a specific diagnosis still cannot be established after bronchoscopy, then a surgical biopsy should be considered (1). It should be borne in mind that the risk of complications rises continuously from BAL (0.12%) to transbronchial biopsy (2.7%) to surgical lung biopsy (8%) (e12, e13, e14), even though such a stepwise approach tends to lower the complication rate (e15).

eBox 5

Bronchoalveolar lavage and transbronchial lung biopsy to diagnose interstitial lung disease associated with an autoimmune disorder

Monitoring

After diagnosing ILD, therapy (ideally evidence-based) must be initiated and the further course must be monitored with regular follow-up examinations. For this purpose, regular clinical and lung-function follow-up of the ILD is recommended every three to six months (1). The FVC plays an essential role in this respect. Thus, progressive fibrotic ILD is defined, amongst other things, by the relative or absolute decline in FVC (3, 14, 15, 16) (eTable 3). HRCT follow-up scans are advisable every 12 to 24 months, depending on the individual risk and clinical course. They may even be warranted sooner if clinical or lung-function findings indicate ILD progression (1, 3).

eTable 3

Different definitions of progressive pulmonary fibrosis (PPF)

Therapy

A literature search identified 11 RCTs evaluating the treatment of AID-ILD, with FVC as the primary endpoint. Since tocilizumab has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of SSc-ILD based on the study by Khanna et al., this study is also listed in eTable 4, even though FVC was only a secondary endpoint (17). The detailed body of evidence (AID, therapeutic intervention, primary endpoint, outcomes, and adverse drug reactions) is presented in Table 2 and in eTable 4.

Table 2

Overview of immunomodulatory treatment options approved in Germany for interstitial lung disease in autoimmune diseases

eTable 4

Overview of immunomodulatory treatment options for interstitial lung disease in autoimmune disease not approved in Germany or not confirmed in randomized controlled trials

General measures

General measures should, on the one hand, improve the patient’s quality of life and, on the other, lower the complication rate. This includes regular vaccinations (e16) and exercise training in particular (e17). Given that patients with ILD have an increased infection risk, especially for pneumonia (e18), basic immunization against Haemophilus influenzae and pneumococci (a single dose of PCV20) and annual immunization against influenza and COVID-19 should be ensured (e16). As of late, respiratory syncytial virus (RSV) vaccination is recommended for ILD patients aged 60 years and older (e19).

It should be noted here that in most cases rituximab will result in an absent humoral vaccine response to new antigens for the following six to eight months after the last application. No restrictions apply to the other immunomodulatory agents used in ILD treatment with respect to inactivated vaccines. However, live-attenuated vaccines should not be administered to patients receiving high-dose glucocorticoids (prednisolone equivalent >20 mg/day), cyclophosphamide, other classic immunosuppressants, and biological agents such as tocilizumab.

The indication for long-term oxygen therapy must be established in patients with respiratory failure, especially when associated with progressive ILD, in accordance with the S2k guideline on long-term oxygen therapy of the German Society for Pneumology and Respiratory Medicine (e20). After diagnosis and completion of treatment, patients with ILD should also be offered pulmonary rehabilitation (e21). The option of timely lung transplantation should always be considered for patients with progressive fibrotic ILD. They should be referred to an appropriate lung transplant center for this purpose. If none of these options apply, then palliative care should be discussed with the patient as soon as possible (e22).

Pharmacotherapy

Both immunomodulatory and antifibrotic therapeutic approaches are available for the pharmacological treatment of AID-ILD. A combination of both approaches is also possible if required. Clinical and laboratory parameters, HRCT pattern (inflammatory versus fibrotic), histopathological features, and other organ manifestations (e.g., heart and kidney), among other factors, should be considered during decision-making (16). Disease-dependent organ screening is appropriate for assessing additional organ involvement (e8). Available data on the treatment of autoimmune-related ILD are limited due to the heterogeneity of AID, but this is gradually changing.

Table 2 provides a summary of treatment principles currently approved for Germany, while eTable 4 and eBox 6 present treatment options not approved in Germany. The therapy decision should be reached by interdisciplinary collaboration (ILD board) and with the involvement of rheumatologists (1, 16), with the primary goal of preventing organ damage.

eBox 6

Pharmacological treatment options for interstitial lung disease associated with an autoimmune disorder

eBox 7

Areas of priority for future research focusing on interstitial lung disease in autoimmune-mediated diseases

Immunomodulatory therapy

Given that the inflammation driven by the autoimmune process is initially of paramount concern, the indication for immunomodulatory therapy should always be assessed (18, 19, 20). The use of high-dose glucocorticoids (more than 10–15 mg mg/day of prednisolone equivalent) should be strictly avoided in patients with SSc due to the risk of developing a renal crisis. On the other hand, an initial dose of 10 to 15 mg per day of prednisolone equivalent is definitely too low for the effective treatment of SSc-ILD; no reliable data demonstrate efficacy even at higher doses. However, systemic glucocorticoids are often still justified for other forms of AID, provided they are quickly reduced and used in combination with another immunomodulatory medication (20).

Immunomodulatory therapy specifically for ILD has not been approved in Germany. However, cyclophosphamide has received general approval for the treatment of life-threatening AID. One RCT showed a significant decrease in FVC decline in patients with SSc-ILD over 12 months under treatment with cyclophosphamide (−1.0 ± 0.9%) in comparison with placebo (−2.6 ± 0.9 % (e7). Patients with ILD associated with anti-synthetase syndromes also benefited from this form of therapy (e23). Rituximab, on the other hand, is approved for the treatment of small vessel vasculitis with pulmonary involvement (21, 22). There is, however, no separate regulatory approval for ILD, although several small RCTs involving cyclophosphamide have shown comparable therapeutic effects (Table 2, eTable 4) (23, 24, 25).

Antifibrotic therapy

Since the extension of approval for nintedanib in 2020, this medication is not only available for patients with IPF but also for those with other forms of chronic progressive fibrotic ILD or progressive pulmonary fibrosis (PPF) of various etiologies (eTable 3). The indication exists when ILD progression is confirmed, although definitions vary (eTable 3). Based on the SENSCIS trial, approval for treatment with nintedanib is also granted at the initial diagnosis of SSc-ILD (26). Regardless of the underlying AID, antifibrotic therapy reduces the loss of lung function by around one half, thus delaying ILD progression. More information on this is available in eBox 6.

Prognosis

The presence of ILD is central to prognosis across all AIDs. An age- and sex-adjusted analysis showed that patients with RA-associated ILD had a higher mortality rate than other patients with RA (five-year mortality 39.0% with ILD vs. 18.2% without ILD) (e24). Comparable ILD data are also available for SSc (hazard ratio [HR] 2.6) (e25), pSS (relative risk [RR] 2.54; 95% confidence interval [1.28; 5.04]) (e26), IIM (HR 2.13 [1.06; 4.25]) (e27), and ANCA-associated vasculitis (RR 2.90 [1.77; 4.74]) (e28). Patients with an AID-ILD who fulfill the criteria of a PPF survive for four years in comparison with eight to ten years in patients with an ILD without PPF criteria (e29). An early diagnosis of an AID-ILD, close monitoring, and appropriate therapy appear to have a significant effect on prognosis.

Dedication

We dedicate this article to the honorable memory of Prof. Dr. med. Dr. rer. nat. Claus Kroegel (1955–2020). As the holder of the Chair of Internal Medicine/Pulmonology at the Friedrich Schiller University of Jena and long-time head of the Department of Pulmonology at Jena University Hospital, he had a decisive influence on the field of pulmonology.

His wealth of knowledge, untiring investigative spirit, empathetic mentorship, and collegiality have left a lasting impression on students, staff, and the scientific community. Professor Kroegel’s legacy in the field of medicine will continue to accompany us as a source of inspiration and incentive for future research and clinical inspiration.

Conflict of interest statement

TH received fees for lectures and travel expenses from Boehringer Ingelheim.

MA received consulting fees and presentation allowances from Boehringer Ingelheim. He is a board member of the German Society for Rheumatology.

DK received consulting fees from the Advisory Boards of Boehringer Ingelheim, Sanofi Aventis, and AstraZeneca. He was granted funds for lectures by Boehringer Ingelheim, Astra Zeneca, Chiesi, GSK, Novartis, and Sanofi Aventis. He received travel expense support for congresses from Boehringer Ingelheim, Sanofi Aventis, and Astra Zeneca.

TH received lecture and consulting fees from Boehringer Ingelheim and is a member of its Advisory Board.

TH received lecture and consulting fees from Boehringer Ingelheim.

GW declares that no conflict of interest exists.

Manuscript received on November 27, 2024, revised version accepted on September 10, 2025

Translated from the original German by Dr. Grahame Larkin

Corresponding author:
Prof. Dr. med. Alexander Pfeil

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