The majority of connective tissue diseases (CTDs) are multisystem disorders that are often heterogeneous in their presentation and do not have a single laboratory, histologic, or radiologic feature that is defined as the gold standard to support a specific diagnosis. Given this challenging situation, the diagnosis of CTD is a process that requires the synthesis of multidisciplinary data which may include patient clinical symptoms, serologic evaluation, laboratory testing, and imaging. Pulmonary manifestations of connective tissue disease include interstitial lung disease as well as multicompartmental manifestations. These CT imaging patterns and features of specific diseases will be discussed in this article.

BACKGROUND: Anti-neutrophil cytoplasmic antibody (ANCA) is a type of autoantibodies associated with vasculitis. ANCA positivity is commonly observed in interstitial lung disease (ILD) patients. 7%-10% of ANCA-positive ILD patients don\'t present any symptoms of systemic vasculitis and are termed ANCA-positive idiopathic interstitial pneumonia (ANCA-IIP). Some researchers propose that ANCA-IIP should be categorized as interstitial pneumonia with autoimmune features (IPAF), although the official ATS/ERS statements exclude ANCA-IIP from this classification. Whether ANCA-IIP should be categorized into the entity of IPAF is still debatable.
METHODS: Patients diagnosed with ANCA-IIP and those with IPAF were analyzed in a retrospective study of ILD. The clinical outcomes were determined through pulmonary function tests (PFTs) after a one-year follow-up, as well as assessing all-cause mortality.
RESULTS: 27 patients with ANCA-IIP and 143 patients with IPAF were analyzed from a cohort of 995 patients with ILD. Patients in the ANCA-IIP group had an older age and a high proportion of males compared to those in the IPAF group. PFT results at baseline were similar between the two groups, except for a better FEV1% in the ANCA-IIP group. Glucocorticoid and immunosuppressive therapy improved pulmonary function in patients with IPAF, but it continued to deteriorate after one year of treatment in the ANCA-IIP group. Furthermore, the all-cause mortality rate was significantly higher in the ANCA-IIP group than in the IPAF group (22.2% vs. 6.3%, P = 0.017).
CONCLUSIONS: The responses to glucocorticoid and immunosuppressive therapy differ between the ANCA-IIP and IPAF groups, leading to divergent prognoses. Therefore, it is inappropriate to classify ANCA-IIP as part of IPAF.

Nodal T-follicular helper cell lymphoma (nTFHL), a hematologic neoplasm originating from T-follicular helper (TFH) cells, occasionally presents with pulmonary radiographic abnormalities, without neoplastic cellular infiltration. However, the precise mechanisms underlying non-neoplastic pulmonary opacities in patients with nTFHL remain unclear. Previous reports have shown that TFH cell abnormalities are associated with collagen disease and interstitial pneumonia with autoimmune features (IPAF). We herein report a patient with nTFHL accompanied by interstitial pneumonia diagnosed via lung and lymph node biopsies. These findings suggest the need to rule out nTFHL before diagnosing IPAF.

While idiopathic interstitial pneumonia (IIP) centering on idiopathic pulmonary fibrosis (IPF) is the most prevalent interstitial lung disease (ILD), especially in the older adult population, connective tissue disease (CTD)-related ILD is the second most prevalent ILD. The pathogenesis of IPF is primarily fibrosis, whereas that of other ILDs, particularly CTD-ILD, is mainly inflammation. Therefore, a precise diagnosis is crucial for selecting appropriate treatments, such as antifibrotic or immunosuppressive agents. In addition, some patients with IIP have CTD-related features, such as arthritis and skin eruption, but do not meet the criteria for any CTD, this is referred to as interstitial pneumonia with autoimmune features (IPAF). IPAF is closely associated with idiopathic nonspecific interstitial pneumonia (iNSIP) and cryptogenic organizing pneumonia (COP). Furthermore, patients with iNSIP or those with NSIP with OP overlap frequently develop polymyositis/dermatomyositis after the diagnosis of IIP. Acute exacerbation of ILD, the most common cause of death, occurs more frequently in patients with IPF than in those with other ILDs. Although acute exacerbation of CTD-ILD occurs at a low rate of incidence, patients with rheumatoid arthritis, microscopic polyangiitis, or systemic sclerosis experience more acute exacerbation of CTD-ILD than those with other CTD. In this review, the features of each IIP, focusing on CTD-related signatures, are summarized, and the pathogenesis and appropriate treatments to improve the prognoses of patients with various ILDs are discussed.

BACKGROUND: Patients with idiopathic interstitial pneumonia (IIP) have a favourable prognosis when they have interstitial pneumonia with autoimmune features (IPAF). However, precise IPAF-related findings from high-resolution computed tomography (HRCT) and lung histopathological specimens and the treatment response have not been fully determined. Therefore, this study was conducted to evaluate the relationship between findings on HRCT or lung histopathological specimens and the progression of interstitial pneumonia in patients with IPAF.
METHODS: This multicentre cohort study prospectively enrolled consecutive patients with IIP. At the diagnosis of IIP, we systematically evaluated 74 features suggestive of connective tissue diseases and followed them up. HRCT, lung specimens, serum antibodies, and the clinical course were also evaluated.
RESULTS: Among 222 patients with IIP, 26 (11.7%) fulfilled the IPAF criteria. During a median observation period of 36 months, patients with IPAF showed better survival than those without IPAF (p = 0.034). While histopathological findings were not related to IPAF, nonspecific interstitial pneumonia (NSIP) with organizing pneumonia (OP) overlap was the most prevalent HRCT pattern (p < 0.001) and the consolidation opacity was the most common radiological finding in IPAF (p = 0.017). Furthermore, in patients with IPAF, the diagnosis of COP or NSIP with OP overlap was associated with a higher increase in %FVC in 1 year than in those with idiopathic pulmonary fibrosis, NSIP, or unclassifiable IIP (p = 0.002).
CONCLUSIONS: This study shows the presence of consolidation opacity on HRCT and the diagnosis of COP or NSIP with OP overlap are associated with IPAF and its favourable treatment response in patients with IPAF.

BACKGROUND: We proposed the term \"UIPAF\" to define patients with Usual Interstitial Pneumonia (UIP) associated with only one domain of the classification called \"Interstitial Pneumonia with Autoimmune Features\" (IPAF). The objective of this study was to evaluate the clinical presentation and prognosis of UIPAF patients, compared with two cohorts, composed of IPAF and idiopathic pulmonary fibrosis (IPF) patients, respectively.
METHODS: The patients were enrolled as IPAF, UIPAF, or IPF based on clinical, serological, and radiological data and evaluated by a multidisciplinary team.
RESULTS: We enrolled 110 patients with IPF, 69 UIPAF, and 123 IPAF subjects. UIPAF patients were similar to IPAF regarding autoimmune features, except for the prevalence of Rheumatoid Factor in UIPAF and anti-SSA in IPAF. A similar proportion of the two cohorts progressed toward a specific autoimmune disease (SAD), with differences in the kind of SAD developed. The real-life management and prognosis of UIPAF patients proved to be almost identical to IPF.
CONCLUSIONS: UIPAF shared with IPAF similar autoimmune features, suggesting the opportunity to be considered IPAF, excluding the morphological domain by the classification. However, the real-life management and prognosis of UIPAF are similar to IPF. These data suggest a possible modification in the therapeutic management of UIPAF.

BACKGROUND: Interstitial pneumonia with autoimmune features (IPAF) has features of connective tissue disease-associated interstitial lung disease (CTD-ILD), but without meeting criteria for a specific CTD. We compared baseline characteristics, survival, and response to treatment of IPAF to both CTD-ILD and unclassifiable ILD.
METHODS: Measurements were extracted from a prospective registry. Baseline features and survival were compared in IPAF against both CTD-ILD and unclassifiable ILD. Linear trajectory of lung function decline (%-predicted forced vital capacity [FVC%] and diffusion capacity of the lung for carbon monoxide [DLCO%]) before and after initiation of mycophenolate or azathioprine were compared in IPAF against both CTD-ILD and unclassifiable ILD using linear mixed models.
RESULTS: Compared to CTD-ILD (n = 1240), patients with IPAF (n = 128) were older, more frequently male, and had greater smoking history. Compared to unclassifiable ILD (n = 665), patients with IPAF were younger, more frequently female, and had worse baseline lung function. IPAF had higher mortality compared to CTD-ILD and similar risk of mortality compared to unclassifiable ILD. Mycophenolate initiation was associated with stabilization of FVC% and DLCO% in all ILD subtypes except for FVC% in patients with IPAF, and azathioprine initiation with stabilization of FVC% and DLCO% in all ILD subtypes except for FVC% decline in IPAF and DLCO% decline in CTD-ILD.
CONCLUSIONS: Patients with IPAF had worse survival compared to those with CTD-ILD and similar mortality to unclassifiable ILD, with treatment being associated with stabilization in lung function in all three ILDs. It is uncertain whether IPAF should be considered a distinct ILD diagnostic subgroup.

BACKGROUND: \"Interstitial lung disease\" (ILD) is a broad term encompassing diseases of different backgrounds. \"Interstitial pneumonia with autoimmune features\" (IPAF) is a recent term that implies the presence of autoimmunity.
OBJECTIVE: This study aims to determine the characteristics of Polish patients with IPAF, compare them with patients with other interstitial pneumonias, and search for the prognostic and diagnostic biomarkers of IPAF in serum and bronchoalveolar lavage fluid (BALF).
METHODS: This multicenter prospective study plans to recruit 240 participants divided into 1 study group and 2 control groups. Biological fluid samples will be collected according to Polish Respiratory Society management guidelines and stored at -80°C for further tests. Prospective 5-year observations of 60 newly diagnosed individuals are planned. The study will be divided into subsections. First, we plan to characterize Polish patients with IPAF (study group) against their peers with other ILDs (2 control groups). Control group 1 will comprise patients with idiopathic ILDs, including mainly idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia. Control group 2 will comprise patients with connective tissue disease-associated interstitial lung diseases, such as rheumatoid arthritis, systemic sclerosis, polymyositis, dermatomyositis, Sjögren\'s syndrome, mixed connective tissue disease, and systemic lupus erythematosus. Radiological and functional parameters will be analyzed. Patients will be compared in terms of high-resolution computed tomography results, the 6-minute walking test performance, and pulmonary function test parameters. The diagnosis of IPAF will be reassessed on a regular basis through multidisciplinary discussion in order to determine its clinical stability. In the laboratory arm, inflammation and fibrosis pathways will be assessed. Cytokine levels (interleukin 8, transforming growth factor beta 1, chemokine C-C motif ligand [CXCL]18, CXCL1, surfactant protein [SP]-A, SP-D, Krebs von den Lungen-6 protein, and chitinase 1) will be measured in serum and BALF. A comparative analysis of serum and BALF cytokine levels will be performed in order to establish potential differences between systemic and local inflammatory pathways. In the quality of life (QoL) arm of the study, dyspnea and cough and their impact on various aspects of the QoL will be assessed. Depression and anxiety will be measured with the Hospital Anxiety and Depression Modified Scale and the 9-item Patient Health Questionnaire, and potential correlations with symptom prevalence will be assessed.
RESULTS: This study will start recruiting patients to phase 1 in October 2023. The final results will be available in 2028. We plan to publish preliminary results after 2-3 years from the start of phase 1.
CONCLUSIONS: This study will be a step toward a better understanding of IPAF etiopathogenesis and outcomes.
UNASSIGNED: PRR1-10.2196/44802.

OBJECTIVE: To explore whether cytokines could be potential biomarkers to predict the occurrence of the progressive fibrosis (PF) phenotype among patients with interstitial pneumonia with autoimmune features (IPAF).
METHODS: This study prospectively collected 51 IPAF and 15 idiopathic pulmonary fibrosis (IPF) patients who were diagnosed at the First Affiliated Hospital of Guangzhou Medical University from July 2020 to June 2021. All IPAF patients were followed up for 1 year to assess the development of PF phenotype. Paired bronchoalveolar lavage fluid (BALF) and serum samples were collected at enrolment and analysed for differences in 39 cytokines expression. Principal component analysis (PCA) and cluster analysis were conducted to identify a subgroup of IPAF patients at high risk for developing the PF phenotype. Finally, cytokine differences were compared between subgroups to identify potential biomarkers for PF-IPAF occurrence.
RESULTS: According to the PCA analysis, 81.25% of PF-IPAF patients share overlapped BALF cytokine profiles with IPF. Cluster analysis indicated that IPAF patients in subtype 2 had a higher risk of developing the PF phenotype within 1 year (P = 0.048), characterized by higher levels of CCL2 and CXCL12, and lower lymphocyte proportion (LYM%) in BALF. Elevated levels of BALF CCL2 (>299.16 pg/ml) or CXCL12 (>660.115 pg/ml) were associated with a significantly higher risk of developing PF phenotype within the 1-year follow-up period (P = 0.009, 0.001, respectively).
CONCLUSIONS: PF-IPAF phenotype exhibits similar inflammatory cytokine profiles to IPF. Cytokine CCL2 and CXCL12, and LYM% in BALF serve as potential biomarkers for predicting the PF phenotype in IPAF patients.
BACKGROUND: Register: Qian Han, Website: http://www.chictr.org.cn/showproj.aspx?proj=61619, Registration number: ChiCTR2000040998.

OBJECTIVE: To assess the ability of two risk prediction models in interstitial lung disease (ILD) to predict death or lung transplantation in a cohort of patients with interstitial pneumonia with autoimmune features (IPAF).
METHODS: We performed a retrospective cohort study of adults with IPAF at an academic medical centre. The primary outcome was a composite of lung transplantation or death. We applied the patient data to the previously described Gender-Age-Physiology (GAP) and ILD-GAP models to determine the ability of these models to predict the composite outcome. Model discrimination was assessed using the c-index, and model calibration was determined by comparing the incidence ratios of observed vs expected deaths.
RESULTS: Ninety-four patients with IPAF were included. Mean (s.d.) age was 58 (13.5) years and the majority were female (62%). The majority met serologic and morphologic criteria for IPAF (94% and 91%, respectively). The GAP model had a c-index of 0.664 (95% CI 0.547-0.781), while the ILD-GAP model had a c-index of 0.569 (95% CI 0.440-0.697). In those with GAP stage 1 or GAP stage 2 disease, calibration of the GAP model was satisfactory at 2 and 3 years for the cumulative end point of lung transplantation or death.
CONCLUSIONS: In patients with IPAF, the GAP model performed well as a predictor of lung transplantation or death at 2 years and 3 years from ILD diagnosis in patients with GAP stage 1 and GAP stage 2 disease.