Pulmonary Involvement in Autoimmune-Mediated Disease

Summary

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.

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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 (1-3). 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-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.

Search term	MESH term	Number	Relevant 1
Interstitial lung disease general, search period 2005 to 2024
(“interstitial lung disease” OR “lung involvement” OR “pulmonary involvement” OR “ILD”) AND (2005:2024[pdat])	(“interstitial lung disease”[AII Fields] OR “lung involvement”[AII Fields] OR “pulmonary involvement”[AII Fields] OR “ILD”[AII Fields]) AND 2005/01 /01:2024/12/31 [Date - Publication]	22018
	AND (meta-analysis[Filter] OR randomizedcontrolledtrial[FiIter])	585
((autoimmune disease) OR (immune-mediated inflammatory diseases)) AND (2005:2024[pdat])	((“autoimmune diseases”[MeSH Terms] OR (“autoiimmune”[All Fields] AND “diseases”[AII Fields]) OR “autoimmune diseases”[AII Fields] OR (“ au toi m mu ne” [A II Fields] AND “disease” [Al I Fields]) OR “autoimmune di sease” [A II Fields] OR (“i m mu ne-medi ated” [Al I Fields] AND (“inflamma- tories”[AII Fields] OR “inflammatory”[AII Fields]) AND (“disease”[MeSH Terms] OR “disease”[AII Fields] OR “diseases”[AII Fields] OR “disease s”[AII Fields] OR “diseased”[AII Fields]))) AND 2005/01/01:2024/12/31 [Date - Publication]) AND (2005:2025[pdat])	379 830
	AND (meta-analysis[Filter] OR randomizedcontrolledtrial[FiIter])	14 466
(“interstitial lung disease” OR “lung involvement” OR “pulmonary involvement” OR “ILD”) AND ((autoimmune disease) OR (immune-mediated inflammatory diseases)) AND (2005:2024[pdat])	((“interstitial lung disease”[AII Fields] OR “lung involvement”[AII Fields] OR “pulmonary involvement”[All Fields] OR “ILD”[AII Fields]) AND (“autoimmune diseases”[MeSH Terms] OR (“autoimmune”[AII Fields] AND “diseases”[AII Fields]) OR “autoimmune diseases”[AII Fields] OR (“ autoi m mu ne” [A II Fields] AND “disease” [Al I Fields]) OR “autoimmune di sease” [A II Fields] OR (“i m mu ne-medi ated” [Al I Fields] AND (“inflamma- tories”[AII Fields] OR “inflammatory”[AII Fields]) AND (“disease”[MeSH Terms] OR “disease”[AII Fields] OR “diseases”[AII Fields] OR “disease s”[AII Fields] OR “diseased”[AlI Fields])))) AND (2005:2024[pdat])	3559
	AND (meta-analysis[Filter] OR randomizedcontrolledtrial[FiIter])	69
Search in abstracts and titles of 3559 articles for:
IBD, inflammatory bowel disease, colitis, crohn	no meta-analyses or RCTs, 3 case reports	38	3
autoimmune hepatitis, autoimmune liver disease	no meta-analyses or RCTs, 1 review, 1 case report	23	2
multiple sclerosis, neuritis	no meta-analyses or RCTs, 1 case report	27	1
spondyloarthritis, psoriatic arthritis, psoriasis	no meta-analyses or RCTs, 5 case reports, 1 retrospective study (based on ICD 10 coding), 1 observation cohort study (with control group from the general population, based on ICD 10 coding), 1 single-center study	38	8
ANCA, vasculitis	no meta-analyses or RCTs, 25 reviews, 5 prospective studies, 60 retrospective studies, 6 case reports	367	96
lgG4-related disease	no meta-analyses or RCTs, 3 case reports	3	3
antiphospholipid syndrome, antiphospholipid antibody	no meta-analyses or RCTs, 2 case reports, 6 retrospective studies, 1 review	37	9
autoimmune endocrine disease (type 1 diabetes, thyroiditis, adrenalitis, Addison’s disease)	no meta-analyses or RCTs, 1 case report	9	1
autoimmune cytopenias (immune thrombocytopenias (ITP), forms of autoimmune hemolytic anemia [A I HA])	no meta-analyses or RCTs, 1 case report	1	1
Inflammatory rheumatic diseases			Of 183 original articles, 163 remained after removal of duplicates
inflammatory rheumatic disease AND (2005:2025[pdat])	(“inflammatories”[AII Fields] OR “inflammatory”[AII Fields]) AND (“rheumatic diseases”[MeSH Terms] OR (“rheumatic”[AII Fields] AND “diseases” [All Fields]) OR “rheumatic diseases”[AII Fields] OR (“rheumatic”[All Fields] AND “disease”[AII Fields]) OR “rheumatic disease”[All Fields]) AND 2005/01/01:2025/12/31 [Date - Publication]	34 020
(“interstitial lung disease” OR “lung involvement” OR “pulmonary involvement” OR “ILD”) AND (inflammatory rheumatic disease) AND (2005:2025 [pdat])	(“interstitial lung disease”[AII Fields] OR “lung involvement”[AII Fields] OR “pulmonary involvement”[AII Fields] OR “ILD”[AII Fields]) AND ((“inflammatories”[AII Fields] OR “inflammatory”[AII Fields]) AND (“rheumatic diseases”[MeSH Terms] OR (“rheumatic”[AII Fields] AND “diseases” [All Fields]) OR “rheumatic diseases”[AII Fields] OR (“rheumatic”[All Fields] AND “disease”[AII Fields]) OR “rheumatic disease”[All Fields])) AND 2005/01/01:2025/12/31 [Date - Publication]	328
	AND (meta-analysis[Filter] OR randomizedcontrolledtrial[FiIter])	6
Rheumatoid arthritis
rheumatoid arthritis AND (2005:2025[pdat])	((“arthritis, rheumatoid”[MeSH Terms] OR (“arthritis”[All Fields] AND “rheumatoid”[AII Fields]) OR “rheumatoid arthritis”[AII Fields] OR (“rheu- matoid”[AII Fields] AND “arthritis”[AII Fields])) AND 2005/01/01:2025/12/31 [Date - Publication]) AND (2005:2025[pdat])	96 099
(“interstitial lung disease” OR “lung involvement” OR “pulmonary involvement” OR “ILD”) AND rheumatoid arthritis AND (2005:2025[pdat])	(“interstitial lung disease”[AII Fields] OR “lung involvement”[AII Fields] OR “pulmonary involvement”[AII Fields] OR “ILD”[AII Fields]) AND (“arthritis, rheumatoid”[MeSH Terms] OR (“arthritis”[AII Fields] AND “rheumatoid”[AII Fields]) OR “rheumatoid arthritis”[AII Fields] OR (“rheu- matoid”[AII Fields] AND “arthritis”[AII Fields])) AND 2005/01/01:2025/12/31 [Date - Publication]	1784
	AND (meta-analysis[Filter] OR randomizedcontrolledtrial[FiIter])	41
Myositis
myositis AND (2005:2025[pdat])	(“myositis”[MeSH Terms] OR “myositis”[All Fields] OR 11 myositides”[AII Fields]) AND (2005:2024[pdat])	15 526
(“interstitial lung disease” OR “lung involvement” OR “pulmonary involvement” OR “ILD”) AND myositis AND (2005:2025[pdat])	(“interstitial lung disease”[AII Fields] OR “lung involvement”[AII Fields] OR “pulmonary involvement”[AII Fields]) AND (“myositis”[MeSI-l Terms] OR “myositis”[AII Fields] OR “myositides”[AII Fields]) AND 2005/01/01:2025/12/31 [Date - Publication]	1830
	AND (meta-analysis[Filter] OR randomizedcontrolledtrial[FiIter])	28
Mixed connective tissue diseases
(connective tissue disease OR CTD) AND (2005:2025[pdat])	(“connective tissue diseases”[MeSH Terms] OR (“connect!ve”[All Fields] AND “tissue”[AII Fields] AND “diseases”[AII Fields]) OR “connective tissue diseases”[AII Fields] OR (“connective”[AII Fields] AND “tissue”[AII Fields] AND “disease”[AII Fields]) OR “connective tissue disease”[AII Fields] OR “CTD”[AII Fields]) AND 2005/01 /01:2025/12/31 [Date - Publication]	185 707
(“interstitial lung disease” OR “lung involvement” OR “pulmonary involvement” OR “ILD”) AND (connective tissue disease OR CTD) AND (2005:2025[pdat])	(“interstitial lung disease”[AII Fields] OR “lung involvement”[AII Fields] OR “pulmonary involvement”[AII Fields] OR “ILD”[AII Fields]) AND (“connective tissue diseases”[MeSH Terms] OR (“connect!ve”[All Fields] AND “tissue”[AII Fields] AND “diseases”[AII Fields]) OR “connective tissue diseases”[AII Fields] OR (“connective”[AII Fields] AND “tissue”[AII Fields] AND “disease”[AII Fields]) OR “connective tissue disease”[AII Fields] OR “CTD”[AII Fields]) AND 2005/01 /01:2025/12/31 [Date - Publication]	5457
	AND (meta-analysis[Filter] OR randomizedcontrolledtrial[FiIter])	172

During the literature review, the titles of the articles were first screened for relevance to the topic, then the abstracts, and finally the full text. A search using the terms “autoimmune hepatitis,” “inflammatory bowel disease,” and “multiple sclerosis” produced no relevant publications. After removing duplicates and publications not covering the topic, a total of 163 relevant articles were identified using the additional search terms; however, only a small number were randomized controlled or Phase III trials.

RCT, randomized controlled trial

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.

Group	Disease	Auto-Ab	Prevalence of the disease (reference)	Estimated ILD prevalence [95% CI] (reference)	CT pattern, adapted from (4)
					UIP	NSIP	OP	other
Rheumatology	Rheumatoide arthritis	yes	0.8-1.2% (e30)	11% [7; 15] (4)	++++	+++	(+)	+
	Primary Sjögren’s syndrome	yes	0.07% (e30)	17% [12; 21] (4)	++	++++	(+)	+
	Systemic lupus erythematosus	yes	0.056% (e30)	6% [3; 10] (4)	(+)	++	(−)	++++
	Systemic sclerose	yes	0.017-0.025% (e30)	47% [44; 50] (4)	+	++++	(−)	(+)
	Idiopathic inflammatory myopathy (myositis)	yes	0.012-0.017% (e30)	41% [33; 50] (4)	(+)	++++	+	+
	ANCA-associated vasculitis	yes	0.015-0.026% (e30)	2-25% (e5)
	Spondyloarthritis	no	1.0-1.4% (e30)	0.35% (e31)*	-
	Psoriatic arthritis	no	0.24-0.32% (e30)	0.21-0.54% (e31, e32)*	-
	Antiphospholipid syndrome	yes	0.04-0.05% (e33)	Case reports	-
	IgG4-related disease	no	0.0052% (e34)	Case reports	-
Hematology	Autoimmune cytopenias (immune thrombocytopenias [ITPs], autoimmune hemolytic anemias)	yes	0.0025-0.017% (e35, e36)	Case reports	-
Endocrinology	Endocrine autoimmune diseases (type 1 diabetes mellitus, thyroiditis, adrenalitis, Addison’s disease)	yes	0.009-9.5% (e37, e38)	Case reports	-
Gastroenterology/ hepatology	Crohn’s disease	no	0.322% (e39)	0.1% (e43)*	-
	Ulcerative colitis	no	0.505% (e39)		-
	Autoimmune hepatitis	yes	0.01-0.03% (e40)	Case reports	-
Neurology	Multiple sclerosis	yes	0.34% (e41)	Case reports	-
Idiopathic pulmonary fibrosis		no	0.01% (e42)	-	-

Rheumatoid arthritis (RA) belongs to the “rheumatological disease” group. The prevalence of RA ranges from 0.8 to 1.2%. In the RA patient group, the estimated ILD prevalence is 11%; 95% CI: [7; 15]. A UIP (>40%) or an NSIP pattern (30 to 40%) is most often detected on high-resolution chest computed tomography.

(−) = very rare; (+) = up to 10%; + = 10 to 2o%; ++ = 20 to 30%; +++ = 30 to 40 %; ++++ = > 40%

^*based on observational studies, no randomly controlled trial or meta-analysis

ANCA, anti-neutrophil cytoplasmatic antibodies; Auto-Ab, auto-antibodies; CT, computed tomography; ILD, interstitial lung disease; CI, confidence interval; NSIP, nonspecific interstitial pneumonia; OP, organizing pneumonia; UIP, usual interstitial pneumonia

eBox 1. Prevalence of interstitial lung disease in patients with spondylarthritis, inflammatory bowel disease, and other immune-mediated disorders.

There does not appear to be significant involvement of interstitial lung disease (ILD) in other essentially immune-mediated diseases (IgG4-related disease, autoimmune endocrinological and hematological disorders); if it occurs at all, only isolated case reports have been reported.

Only a few observational studies on ILD in patients with spondylarthritis are available. They suggest a low prevalence of 0.1-0.2 % as compared with 0.1% ILD in the general population, of which idiopathic pulmonary fibrosis is the most common form with a prevalence of 0.01% (12, e42, e45, e46) (Table 1). Respiratory tract manifestations (tracheitis, bronchitis, bronchiolitis) are also reported in association with inflammatory bowel diseases, as are organizing pneumonia (OP, histological inflammatory reaction of the alveoli associated with intra-alveolar connective tissue proliferations) and granulomatous lung diseases (e47). A drug-induced origin has been suspected in some cases of OP (e48). Retrospective data report only a low prevalence of 0.1% for idiopathic ILD in association with inflammatory bowel disease (e43). Only case reports, case series, and retrospective analyses of ILD are available for disease entities in gastroenterology and neurology; a clear association has not been established (Table 1, eTable 1).

Which immunological-pathophysiological processes specifically lead to the development of ILD in association with AID, and why the occurrence of ILD varies considerably between different underlying diseases, are not fully understood and remain a primary focus for future translational research efforts (eBox 7).

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).

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

(adapted from the S1 guideline on “Interdisciplinary diagnosis of interstitial lung diseases in adults” (1) and ACR/CHEST recommendations 2023 [8]).

eBox 2. Additional information on the risk factors of interstitial lung disease.

In rheumatoid arthritis, a high titer of rheumatoid factor and cyclic anti-citrullinated peptide autoantibodies (odds ratio [OR] 2.11; 95% confidence interval: [1.65; 2.68]), older age (weighted mean difference 6.89; [3.10; 10.67]), and having a smoking history (OR 1.91; [1.48; 2.47]) are associated with an increased risk of interstitial lung disease (8, e49). In systemic sclerosis, male sex and anti-topoisomerase I antibodies (Scl70), amongst other factors, increase the risk (8, 11).

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.

Diagnostic certainty of an ILD can be increased by establishing the diagnosis through a multidisciplinary ILD board in comparison with a diagnosis by a single specialty, as has been shown for the diagnosis of ILD in connective tissue disease (e50): ILD board K = 0.64; clinician K = 0.57; radiologist K = 0.10, and pathologist K = 0.22; K = measure of inter-rater reliability. It should be noted here that there is currently no official overview of existing ILD boards available in Germany. Such an official registry could improve targeted referral pathways and patient care.

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.

Disease	Risk factors
Rheumatoid arthritis	high titer of rheumatoid factors and autoantibodies against cyclic citrulli nated peptides smoking history advanced patient age at initial diagnosis high disease activity male sex high body mass index
Primary Sjögren’s syndrome	anti-Ro52 autoantibodies Raynaud’s symptoms more advanced patient age lymphopenia severe dental caries
Sharp’s syndrome	dysphagia Raynaud’s symptoms other clinical or laboratory features of systemic sclerosis
Systemic sclerose	anti-topoisomerase I antibodies (Scl-70) diffuse cutaneous subtype male sex African American ethnicity early-onset disease (the first 5 to 7 years after initial diagnosis) elevated levels of acute-phase proteins
Idiopathic inflammatory myopathy (myositis)	antisynthetase autoantibodies (Jo-1, PL7, PL12, EJ, OJ, KS, Ha, Zo), furthermore, autoantibodies against MDA-5, Ku, Pm/Scl, Ro52 mechanic’s hands arthritis/arthralgias ulcerating lesions

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.

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.

Ground-glass opacities detected on thin-section lung computed tomography (high-resolution computed tomography, HRCT) are usually the result of inflammation of the alveoli (eFigure a) (e6, e51). Furthermore, the two ILD patterns, i.e., nonspecific interstitial pneumonia (NSIP pattern) (eFigure b) and usual interstitial pneumonia (UIP pattern) (eFigure c), must be distinguished from each other (1, 4, e51). Fibrosis is the main feature of the UIP pattern, while the NSIP pattern may exhibit fibrotic elements to varying degrees, in addition to an inflammatory component (e51, e52). Consolidations are also possible—histo- morphologically, usually reflecting organizing pneumonia (OP)—and at times also overlap with an NSIP pattern (NSIP with OP overlap) (1, 4, e51) (Table 1).

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 (eBox 5). 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-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.

Bronchoalveolar lavage (BAL) helps clarify important differential diagnoses, such as infections. Assessment of the cell pattern (lymphocytic, eosinophilic, or neutrophilic) is possible, allowing conclusions about relevant inflammatory components (e52–e54). A single-center retrospective trial (n = 245, data acquisition 2011 to 2018, USA) showed that BAL modified the diagnosis in 22% of patients with interstitial lung disease (ILD) (e55). Transbronchial lung biopsy (forceps or cryobiopsy) also allows lung tissue to be obtained for appropriate histopathological assessment. This led to a change in diagnosis for 34% of the patients (e55). The histopathological ILD pattern does not necessarily coincide with the HRCT pattern (3). A specific ILD diagnosis can be established in the majority of patients (88%) by lung biopsy (e56).

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, 14-16) (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 lungfunction findings indicate ILD progression (1, 3).

eTable 3. Different definitions of progressive pulmonary fibrosis (PPF).

II German guideline on PPF (16)	International guideline on PPF (3)
At least 1 of 2 criteria met within 24 months (precondition: > 10% fibrosing ILD on HRCT):	Deterioration of at least 2 of 3 domains within 12 months:
Relative decrease of FVC ≥ 10% or evidence of at least two of the following criteria: increase in respiratory symptoms relative FVC decrease by ≥ 5% increase in fibrosis on HRCT absolute decrease of DLCO by ≥ 15% initiation or increase (≥ 1 L/min) in long-term oxygen therapy inpatient treatment for progressive symptoms or exacerbation deterioration in the six-minute walk test (≥ 50m or 20%) or decline in minimal O2 saturation by >5% or below 88% SpO2	Respiratory symptoms Absolute decrease of FVC ≥ 5% or DLCO ≥10% Radiological ILD progression

DLCO, diffusing capacity for carbon monoxide; FVC, forced vital capacity; HRCT, high-resolution computed tomography; ILD, interstitial lung disease; PPF, progressive pulmonary fibrosis

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.

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.

Active substance	Application	Reference, study type, number of pats, (n), year	Disease	Approval	Primary endpoint	Outcomes	Adverse drug reactions
Immune modulatory
Tocilizumab	subcutaneous	(17) RCT (Phase 3), n = 210, 2020	SSc	∅ approved in Germany and in the USA	skin fibrosis	–primary endpoint: was not reached. –secondary endpoint: tocil- izumab maintained FVC (secondary endpoint) in pats, with early active SSc-ILD (active, defined by elevated levels of acute-phase proteins)		Tocilizumab	Placebo
							Participants with > 1 adverse event	n = 89 (86%)	n = 82 (87%)
							Participants with > 1 infectious adverse event	n = 54 (52%)	n = 53 (0%)
							Participants with reactions at the injection site	n = 8 (8%)	n = 3 (3%)
							Participants with > 1 serious adverse event	n = 13 (13%)	n = 18 (17%)
							Participants with > 1 infectious serious adverse event	n = 2 (2%)	n = 7 (7%)
							Participants with > 1 non-infectious serious adverse event	n = 11 (11%)	n = 11 (10%)
							Termination due to adverse event	n = 3 (3%)	n = 4 (4%)
							Death	n = 1 (1%)	n = 3 (3%)
							Infections	n = 3	n = 8
							Osteomyelitis	n = 1 (1%)	n = 0 (1%)
							Inflammatory diseases of the female upper genital tract	n = 1 (1%)	n = 0 (1%)
							Wound infections	n = 1 (1%)	n = 0 (0%)
							Heart failure	n = 1 (1%)	n = 0 (0%)
							Angina pectoris	n= 1 (1%)	n = 0 (1%)
Mycopheno- late motet¡1	oral	(e57) RCT, n = 142, 2016	SSc	∅ in Germany	Change in FVC (as a percent of the predicted normal value) over the course of 24 months	primary endpoint: no inferiority evident in the progression of lung function (FVC) between mycopheno- late (2.19%; 95% confidence interval: [0.53; 3.84]) and cyclophosphamide (oral) medication (2.88%; [1.19; 4.58]), with better tolerability and less toxicity of myco- phenolate.		Mycopheno- late	Cyclophosphamide oral
							Serious adverse event
							Likely related to the treatment	n = 3 (4%)	n = 7 (10%)
							Associated with underlying disease	n = 9 (13%)	n = 13 (18%)
							Other causes	n = 14 (20%)	n = 6 (8%)
							Unknown cause	n = 3 (4%)	n = 3 (4%)
							Death	n = 5 (7%)	n = 11 (15%)
							Leukopenia	n = 4 (6%)	n = 30 (41%)
							Neutropenia	n = 3 (4%)	n = 5 (7%)
							Thrombocytopenia	n = 0 (0%)	n = 4 (6%)
							Anemia	n = 8 (12%)	n = 13 (18%)
							Hematuria	n = 3 (4%)	n = 2 (3%)
							Pneumonia	n = 5 (7%)	n = 4 (6%)
Rituximab	intravenous	(22) openlabel RCT, n = 60, 2018	Diffuse SSc	∅ approved for an ILD	Change in FVC (as a percent of the predicted normal value) over the course of 6 months	Primary endpoint: rituximab (baseline: 61.30 ± 11.28% at month 6: 67.52 ± 13.59%) showed a significant increase in FVC in patients with diffuse SSc-ILD compared with intravenous cyclophosphamide adminis- tration (baseline: 59.25± 12.96 at month 6: 58.06 ± 11.23)		Rituximab	Cyclophosphamide intravenous
							Infections of the upper respiratory tract	n = 2	n = 2
							Pneumonia	n = 1	n = 4
							Urinary tract infection	n = 1	n = 2
							Herpes Zoster	n = 1	n = 3
							Cholecystitis	n = 1	n = 0
							Premature menopause	n = 0	n = 2
							Gangrene	n = 0	n = 1
							Malignancy	n = 0	n = 1
							Leukopenia	n = 0	n = 2
							Vomiting	n = 0	n = 4
							Infusion reaction	n = 3	n = 0
Rituximab	intravenous	(23) RCT, n = 56, 2021	SSc		Change in mRSS after 24 weeks (endpoint skin)	–primary endpoint: was reached –rituximab (0.09 ±0.96%) showed no decrease in FVC in patients with SSc compared with the placebo group (-2.87 ±1.05%) (secondary endpoint).		Rituximab	Placebo
							Any adverse drug reaction	n = 21 (75%)	n = 15 (58%)
							Any serious adverse event	n = 1 (4%)	n = 1 (4%)
							Serious adverse events leading to termination of the study treatment	n = 1 (4%)	n = 1 (4%)
							Death	n = 0 (0%)	n = 0 (0%)
							Infusion reaction	n = 0 (0%)	n = 0 (0%)
							Infections of the upper respiratory tract	n = 11 (39%)	n = 10 (38%)
							Pulmonary valve disease	n = 5 (18%)	n = 3 (12%)
							Gastroesophageal reflux disease	n = 2 (7%)	n = 6 (23%)
							Enterocolitis	n = 2 (7%)	n = 3 (12%)
							Rise in C-reactive protein	n = 3 (11%)	n = 2 (8%)
							Arthralgias	n = 1 (4%)	n = 4 (15%)
							Skin ulcerations	n = 2 (7%)	n = 3 (12%)
							Diarrhea	n = 3 (11%)	n = 1 (4%)
							Oral mucositis	n = 3 (11%)	n = 0 (0%)
							Low neutrophil count	n = 3 (11%)	n = 0 (0%)
							Low leukocyte count	n = 3 (11%)	n = 0 (0%)
							Dermatitis	n = 0 (0%)	n = 3 (12%)
Rituximab	intravenous	(24) RCT (Phase 2b), n = 101, 2023	SSc, IIM, Sharp’s syndrome		Change in FVC (as a percent of the predicted value) over the course of 24 weeks	Primary endpoint: rituximab (97 ±234 mL) was not superior in improving lung function (FVC) compared with cyclophosphamide (99 ±329 mL); however, fewer adverse reactions oc- curred.		Rituximab	Cyclophosphamide intravenous
							Number of all adverse events	646	445
							Diseases of the blood and lymphatic system	0%	<1%
							Heart diseases	1%	2%
							Ear and labyrinth disorders	<1%	<1%
							Eye disorders	2%	2%
							Gastrointestinal disorders	16%	26%
							General disorders and symptoms at the application site	12%	14%
							Hepatobiliary diseases	<1%	<1%
							Disorders of the immune system	<1%	<1%
							Infections	10%	8%
							Injuries, poisonings and procedure-related complications	1%	1%
							Metabolic and nutritional disorders	1%	1%
							Muscle and connective tissue diseases	9%	7%
							Disorders of the nervous system	8%	11%
							Psychiatric disorders	2%	1%
							Diseases of the kidneys and urinary tract	<1%	1%
							Diseases of the reproductive system and the breast	1%	1%
							Diseases of the airways, the chest, and the mediastinum	23%	15%
							Diseases of the skin and the subcutis	7%	6%
							Surgical and medical measures	0%	< 1%
							Vascular disorders	4%	1%
Antifibrotic
Pirfenidone	oral	(e63) RCT (Phase 2b), n = 127, 2021	General progressive ILD	∅ approved for ILD	Change in FVC (as a percent of the predicted value) over the course of 48 weeks	–premature study termi- nation after slow recruiting, also 29% pats, with RA, SSc, 11M or Sjogren’s syndrome –primary endpoint: a slight, but significant, (p = 0.049) decrease in FVC on pirfenidone (-36.6 ±281.5 mL) was evident in comparison with placebo (-114.4 ±225.3).		Pirfenidon	Placebo
							Number of pats, with serious adverse events	n = 26 (41%)	n = 35 (56%)
							Infections	n = 5 (8%)	n = 10 (16%)
							General illnesses and symptoms at the site of application, including deterioration of the disease	n = 2 (3%)	n = 7 (11%)
							Diseases of the airways, the chest, and the mediastinum	n = 4 (6%)	n = 4 (6%)
							Surgical and medical measures	n = 4 (6%)	n = 2 (3%)
							Heart diseases	n = 1 (2%)	n = 5 (8%)
							Benign, malignant, and unspecified neoplasms (including cysts and polyps)	n = 2 (3%)	n = 3 (5%)
							Injury, poisoning, or procedure-related complications	n = 1 (2%)	n = 2 (3%)
							Nervous system disorders	n = 2 (3%)	n = 0 (0%)
							Muscle and connective tissue diseases	n = 2 (3%)	n = 0 (0%)
							Diseases of the kidneys and urinary tract	n = 1 (2%)	n = 1 (2%)
							Gastrointestinal disorders	n = 1 (2%)	n = 0 (0%)
							Death	n = 1 (2%)	n = 5 (8%)

AID, autoimmune disease; FVC, forced vital capacity; 11M, idiopathic inflammatory myopathy; ILD, interstitial lung disease; mRSS, modified Rodnan skin score; RA, rheumatoid arthritis; RCT, randomized controlled trial; SSc, systemic sclerosis; pats., patients [

Table 2. Overview of Immunomodulatory treatment options approved In Germany for Interstitial lung disease In autoimmune diseases.

Active substance	Administration	Reference, study type, number of pats, (n)	Disease	Approval	Primary endpoint	Outcomes	Adverse drug reactions
Immunmodulatory
Cyclophosphamide	oral	(e7) RCT, n = 158, 2006	SSc	Treatment of life-threatening autoimmune diseases	Change in FVC (% pred.) after 12 months	–primary endpoint: significantly small decline in FVC (−1.0 ±0.92%) as compared with the placebo group (−2.6 ±0.9%) –secondary endpoint - change in TLC: cyclophosphamide group (−0.3 ± 1.82%) vs. placebo group (−2.8 ± 1.2%)	–Significantly more cases of leukopenia and neutropenia on oral cyclophosphamide. –No significant difference between the groups with respect to SAEs.
	IV	(e44) Clinical observational study with RCT control group, n = 302, 2020	SSc			Change in FVC, DLCO and mRSS	–FVC: cyclophosphamide IV (−0.6 ±13.3%) vs. oral (+0.1 ±8.4%) –DLCO: cyclophosphamide IV (−4.3 ±13.0%) vs. oral (−3.9 ±13.5%) –mRSS: cyclophosphamide IV (−1.9±5.9 %) vs. oral (−3.0±.5.8%) –he comparison revealed no significant difference in lung function for SSc-ILD, but there were signs of less toxicity.	–Oral cyclophosphamide produced significantly more cases of leukopenia, hemorrhagic cystitis, and alopecia by the end of treatment. –For SAEs, the group receiving IV cyclophosphamide showed significantly more events (p = 0.025); however, this finding was no longer reproducible after adjustment for covariates.
Rituximab	IV	(21) RCT, n = 197, 2010	ANCA-vascu litis	ANCA-vasculitis as induction and maintenance therapy	Glucocorticoid-free remission after 6 months	–primary endpoint: rituximab (64%) vs. cyclophosphamide (53%) –rituximab was not inferior with respect to ANCA-associated vasculitis..	–No significant difference between the groups –More pats, on cyclophosphamide experienced > 1 SAE than on rituximab: n = 32 (33 %) vs. n = 22 (22 %) (p = 0.01)
Antifibrotic
Nintedanib	oral	(14) RCT (Phase 3), n = 663, 2019 and 2020 (15)	Progressive ILD	Treatment of chronic progressive ILD (of various etiologies)	Annual rate of decline in FVC, assessed after 52 weeks	–primary endpoint: significantly lower decrease in FVC on nintedanib (−80.8± 15.1 mL) vs. placebo group (−187.8±14.8 mL) –subanalysis for autoimmune ILD: 104.0 mL (95% confidence interval: [21.1; 186.9 mL])	–Most common side effects: diarrhea and nausea (at times requiring permanent dose reduction or drug discontinuation) –No group difference for SAE or fatal adverse side effects
		(26) RCT (Phase 3), n = 576, 2019	SSc	Primary treatment of SSc-ILD	Annual rate of decline of FVC, assessed after 52 weeks	–primary endpoint: significantly lower decrease in FVC on nintedanib (−52.4 ± 13.8) vs. placebo group (−93.3± 13.5)	–Most common side effects: diarrhea and nausea –No group difference for SAE or fatal adverse side effects.

ANCA, anti-neutrophil cytoplasmatic antibodies; DLCO, diffusing capacity for carbon monoxide; FVC, forced vital capacity; ILD, interstitial lung disease; IV intravenous; mRSS, modified Rodnan skin score; pats., patients; pred., predicted; RCT, randomized controlled trial; SAE, serious adverse event; SSc, systemic sclerosis; TLC, total lung capacity

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.

Apart from approved treatments, i.e., cyclophosphamide (generally for life-threatening autoimmune disease) and rituximab (for ANCA vasculitis), several other well-established forms of therapy are also available in Germany. Mycophenolate mofetil was not inferior to cyclophosphamide in a randomized controlled trial (RCT), while tocilizumab was effective against systemic sclerosis-associated interstitial lung disease (SSc-ILD) as a secondary endpoint in two RCTs (17, e57). All three substances are backed by recommendations for SSc-ILD by EULAR and the American Thoracic Society (ATS) (18, 19). However, they are not approved by the European Medicines Agency (EMA) for this indication (eTable 4).

Myeloablative autologous stem-cell transplantation may also be considered as a treatment option for patients with rapidly progressive SSc-ILD and previously absent therapeutic response (e58). CAR T-cells directed against CD19 appear to have similar effects, at least in individual cases (e59). This approach is currently undergoing further evaluation in a whole series of clinical trials.

Irrespective of the direct effects of immunosuppressants on ILD in connective tissue diseases, the uninterrupted continuation of immunomodulatory background therapy remains essential, as in rheumatoid arthritis. In this respect, recent data indicate that methotrexate, contrary to previous assumptions, does not increase the risk of developing ILD and may even demonstrate a beneficial effect on the risk for RA-ILD in patients with rheumatoid arthritis (methotrexate use in patients with RA-ILD 60% vs. 83% in those without RA-ILD) (e60, e61). Only for TNF inhibitors is there evidence that they may have an unfavorable effect on the course of RA-ILD (e62).

As regards the various forms of antifibrotic therapy, there is also only limited data available on the efficacy of pirfenidone in patients with AIE-ILD - data that are included in guideline recommendations but have not resulted in EMA approval (16, 20, e63). The reason for this is the premature termination of the clinical trial due to the small number of participants (e63). The same applies to the Phase 2 trial assessing pirfenidone in patients with RA-ILD, where patients receiving pirfenidone showed a slower decline in forced vital capacity (e64). More recently developed forms of antifibrotic therapy are currently undergoing clinical assessment.

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) (23-25).

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 i ncentive for future research and clinical inspiration.

Supplementary material

eFigure 1a–c. With kind permission of the Institute for Diagnostic and Interventional Radiology, Jena University Hospital, Prof. Dr. med. Ulf Teichgräber.

eFigure: Typical imaging patterns of interstitial lung diseases (ILD) in autoimmune-mediated diseases; 1: thin- slice spiral computed tomography of the lungs (HRCT).

a, ground-glass opacities (*)

b, nonspecific interstitial pneumonia (NSIP) with groundglass opacities (*), reticulations (←), and traction bronchiectasis (Δ)

c, usual interstitial pneumonia (UIP) associated with traction bronchiectasis (► ) and honeycombing (♦). (With kind permission of the Institute for Diagnostic and Interventional Radiology, Jena University Hospital, Director: Univ.-Prof. Dr. med. habil. Ulf Teichgräber)

eBox 7. Areas of priority for future research focusing on interstitial lung disease in autoimmune-mediated diseases.

• detailed evaluation of immunopathological processes that lead to interstitial lung disease (ILD) in autoimmune-mediated disease (AID)

• evaluation of the frequency with which an AID is diagnosed during the course of the disease in patients with an initial diagnosis of ILD

• collection of data relating to the frequency of ILD progression

• evaluation of the increased risk for each individual risk factor

• assessment of the diagnostic value of lung ultrasound for the diagnosis and monitoring of ILD

Questions on the article in issue 24/2025:

Pulmonary Involvement in Autoimmune-mediated Disease

The submission deadline for entries is 27 November 2026. Only one answer is possible per question.

Please select the answer that is most appropriate.

• Question 1

  What percentage of patients with systemic sclerosis also present with interstitial lung disease?

  1. 10-14%
  2. 20-24%
  3. 34-40%
  4. 44-50%
  5. 54-70%

• Question 2

  Which of the following symptoms is not mentioned in the article as typical for ILD?

  1. velcro crackles
  2. dyspnea
  3. expectoration
  4. finger clubbing
  5. angina pectoris

• Question 3

  Which statement about DLCO measurement is the most appropriate?

  1. DLCO reduction (<80% of the reference) has no high sensitivity for detecting ILD.
  2. Low DLCO can also be an indication of pulmonary arterial hypertension.
  3. Evidence of reduced DLCO (<80%) in AID patients without pulmonary symptoms obviates the need for an HRCT scan.
  4. DLCO reduction must be very pronounced (<60% of the reference) to have any diagnostic reliability.
  5. The results of DLCO reduction depend very much on the patient’s condition on the day of testing and should therefore be interpreted with caution.

• Question 4

  Which imaging modality represents the gold standard for detecting, characterizing, and monitoring ILD?

  1. HRCT
  2. chest X-ray
  3. magnetic resonance imaging
  4. lung ultrasound
  5. spirometry

• Question 5

  What is the percentage risk of developing complications from surgical lung biopsy?

  1. 1%
  2. 3%
  3. 6%
  4. 8%
  5. 14%

• Question 6

  What should be considered when vaccinating patients with ILD?

  1. The humoral immune response is absent for the first three months after administration of any immunomodulatory substance.
  2. Only live vaccines should be given to patients on high-dose glucocorticoids, cyclophosphamide, or classic
     i mmunosuppressants.
  3. Patients with ILD should not receive seasonal vaccines (against influenza and/or COVID-19).
  4. Pneumococcal vaccination (PCV20) should be repeated annually.
  5. RSV vaccination is recommended from the age of 60.

• Question 7

  For which AID should the use of high-dose glucocorticoids (>10-15 mg/day prednisolone equivalent) be avoided?

  1. rheumatoid arthritis
  2. systemic lupus erythematosus
  3. systemic sclerosis
  4. idiopathic inflammatory myopathy
  5. psoriatic arthritis

• Question 8

  Which drug is approved for the antifibrotic treatment of chronic progressive ILD?

  1. risankizumab
  2. belimumab
  3. omalizumab
  4. nintedanib
  5. dupilumab

• Question 9

  The article reports an age- and sex-adjusted analysis of patients with RA-associated ILD. Which outcome does the article highlight?

  1. Five-year mortality was higher in patients with ILD (39.0% with ILD vs. 18.2% without ILD).
  2. Five-year mortality was higher in patients without ILD (18.2% without ILD vs. 9.0% with ILD).
  3. Five-year mortality differs little between patients with and those without ILD (18.2% with ILD vs. 18.4% without ILD).
  4. It was not possible to compare five-year mortality because overall there was a very small number of deaths during the observation period.
  5. Whereas five-year mortality was more or less the same in patients with and those without ILD (39.0% vs. 38.7%), there was a substantial difference for ten-year mortality (90.1% vs. 42%).

• Question 10

  Which statement about immunomodulatory therapy of ILD is the most appropriate?

  1. Rituximab is the only immunomodulatory drug in Germany to have received separate regulatory approval for ILD.
  2. According to available data from RCTs, cyclophosphamide is contraindicated for ILD.
  3. Cyclophosphamide has been approved for the treatment of life-threatening AID.
  4. According to current evidence on SSc-ILD, cyclophosphamide does not reduce FVC decline over the course of one year.
  5. Methotrexate is the preferred immunomodulatory drug for the treatment of ILD, for which it has received specific approval.