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Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by irreversible scarring of lung tissue, leading to death. Despite recent advancements in understanding its pathophysiology, IPF remains elusive, and therapeutic options are limited and non-curative. This review aims to synthesize the latest research developments, focusing on the molecular mechanisms driving the disease and on the related emerging treatments. Unfortunately, several phase 2 studies showing promising preliminary results did not meet the primary endpoints in the subsequent phase 3, underlying the complexity of the disease and the need for new integrated endpoints. IPF remains a challenging condition with a complex interplay of genetic, epigenetic, and pathophysiological factors. Ongoing research into the molecular keystones of IPF is critical for the development of targeted therapies that could potentially stop the progression of the disease. Future directions include personalized medicine approaches, artificial intelligence integration, growth in genetic insights, and novel drug targets.
Subject(s)
Idiopathic Pulmonary Fibrosis , Humans , Idiopathic Pulmonary Fibrosis/therapy , Idiopathic Pulmonary Fibrosis/genetics , Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/pathology , Precision Medicine/methods , Molecular Targeted Therapy/methods , Epigenesis, Genetic , AnimalsABSTRACT
OBJECTIVES: Systemic Sclerosis (SSc) is characterized by widespread microangiopathy and fibrosis of skin and visceral organs. Left ventricle involvement is usually subclinical, characterized by systolic and/or diastolic dysfunction. The global longitudinal strain (GLS), a validated and reliable technique for the measurement of ventricular longitudinal deformation by means of echocardiography, may detect subclinical systolic dysfunction of SSc myocardium. The improvement of myocardial perfusion by means of intravenous Iloprost administration could ameliorate the contractility of SSc heart. Therefore, we aimed to evaluate GLS in a series of SSc patients prior and after Iloprost infusion. METHODS: Fifteen consecutive SSc patients (age: 54 ± 11 years; 12 females) treated with Iloprost because of the presence/history of digital ulcers underwent echocardiography, including GLS technique. This evaluation was conducted immediately before Iloprost administration and at the end of the 6-h infusion session. RESULTS: Significant improvement in the mean GLS was observed after Iloprost administration (from -13.5 ± 2.5 to -15 ± 3.3; p= 0.011). The echocardiographic data obtained from the four-chamber view showed the best quality for GLS analysis and showed a highly significant improvement of the strain after Iloprost administration (from -13.4 ± 2.2 to -15.6 ± 3; p= 0.001). The degree of GLS improvement did not correlate with any SSc parameters. CONCLUSION: Iloprost administration improved GLS, suggesting that the increase of myocardial perfusion allowed, at least in part, a correction of left ventricular systolic dysfunction. Further studies are needed to confirm these findings, further exploring the mid/long-term effects of Iloprost on myocardial contraction.
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BACKGROUND: Interstitial lung disease (ILD) represents a frequent cause of morbidity and mortality in primary Sjogren syndrome (pSS). However, the prevalence and behavior of pSS-ILD remains incomplete, largely based on retrospective heterogeneous studies. AIM OF THE STUDY: To investigate the prevalence of progressive pulmonary fibrosis (PPF) in a multicentric cohort of patients with pSS-ILD. Additionally, this study explored possible correlations between PPF and clinical, demographic, and serological features of pSS. METHODS: All consecutive patients with pSS-ILD were enrolled in a 6-month period. Clinical, demographic, and serological features of pSS, other than functional and radiological lung features, were collected. Clinical behaviors of ILD other than PPF were also investigated. RESULTS: Seventy-two patients were enrolled. A fibrosing ILD pattern was observed in 65.3% of patients with pSS-ILD; among them, 55.3% showed a PPF. The radiologic pattern (NSIP, UIP, or others) was not associated with PPF; in particular, patients with PFF had UIP in 42.3% of cases and NSIP in 57.7%, without a significant difference with respect to the non-PPF group (p = 0.29). Shorter pSS disease duration, higher age at pSS diagnosis, and lower frequency of antinuclear antibodies were correlated with the PPF subgroup. However, multivariate analysis did not confirm these associations. DISCUSSION: This study provides valuable insights into the prevalence and characteristics of PPF in pSS-ILD. In particular, UIP and NSIP showed a similar evolution towards PPF in patients with pSS; for NSIP, this behavior was more frequent than for other rheumatic diseases. Our results emphasize the importance of early recognition of PPF for timely intervention and careful follow-up. CONCLUSIONS: This study provides valuable insights into the prevalence and characteristics of PPF in pSS-ILD. In particular, UIP and NSIP showed a similar evolution towards PPF in patients with pSS; for NSIP, this behavior was more frequent than for other rheumatic diseases. Our results emphasize the importance of early recognition of PPF for timely intervention and careful follow-up.
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Idiopathic pulmonary fibrosis (IPF) represents a fibrotic interstitial lung disease characterized by uncertain etiology and poor prognosis. Over the years, the path to effective treatments has been marked by a series of advances and setbacks. The introduction of approved antifibrotic drugs, pirfenidone and nintedanib, marked a pivotal moment in the management of IPF. However, despite these advances, these drugs are not curative, although they can slow the natural progression of the disease. The history of drug therapy for IPF goes together with the increased understanding of the pathogenic mechanisms underlying the disease. Based on that, current research efforts continue to explore new therapies, possible personalized treatment strategies, drug combinations, and potential biomarkers for diagnosis and prognosis. In this review, we outline the route that led to the discover of the first effective therapies, ongoing clinical trials, and future directions in the search for more effective treatments.
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OBJECTIVES: The CLASS (Classification Criteria of Anti-Synthetase Syndrome) project is a large international multicentre study that aims to create the first data-driven anti-synthetase syndrome (ASSD) classification criteria. Identifying anti-aminoacyl tRNA synthetase antibodies (anti-ARS) is crucial for diagnosis, and several commercial immunoassays are now available for this purpose. However, using these assays risks yielding false-positive or false-negative results, potentially leading to misdiagnosis. The established reference standard for detecting anti-ARS is immunoprecipitation (IP), typically employed in research rather than routine autoantibody testing. We gathered samples from participating centers and results from local anti-ARS testing. As an "ad-interim" study within the CLASS project, we aimed to assess how local immunoassays perform in real-world settings compared to our central definition of anti-ARS positivity. METHODS: We collected 787 serum samples from participating centres for the CLASS project and their local anti-ARS test results. These samples underwent initial central testing using RNA-IP. Following this, the specificity of ARS was reconfirmed centrally through ELISA, line-blot assay (LIA), and, in cases of conflicting results, protein-IP. The sensitivity, specificity, positive likelihood ratio and positive and negative predictive values were evaluated. We also calculated the inter-rater agreement between central and local results using a weighted κ co-efficient. RESULTS: Our analysis demonstrates that local, real-world detection of anti-Jo1 is reliable with high sensitivity and specificity with a very good level of agreement with our central definition of anti-Jo1 antibody positivity. However, the agreement between local immunoassay and central determination of anti-non-Jo1 antibodies varied, especially among results obtained using local LIA, ELISA and "other" methods. CONCLUSIONS: Our study evaluates the performance of real-world identification of anti-synthetase antibodies in a large cohort of multi-national patients with ASSD and controls. Our analysis reinforces the reliability of real-world anti-Jo1 detection methods. In contrast, challenges persist for anti-non-Jo1 identification, particularly anti-PL7 and rarer antibodies such as anti-OJ/KS. Clinicians should exercise caution when interpreting anti-synthetase antibodies, especially when commercial immunoassays test positive for non-anti-Jo1 antibodies.
Subject(s)
Amino Acyl-tRNA Synthetases , Myositis , Humans , Ligases , Reproducibility of Results , Biological Specimen Banks , Autoantibodies , Myositis/diagnosisABSTRACT
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.
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Remdesivir is one of the most attractive options for patients with hypoxemic respiratory failure due to coronavirus disease 2019 (COVID-19). The aim of our study was to evaluate the effect of remdesivir on the hypoxic and inflammatory state in patients with moderate to severe COVID-19. We retrospectively enrolled 112 patients admitted for COVID-19 pneumonia, requiring low-flow oxygen, 57 treated with remdesivir plus standard of care (SoC) and 55 treated only with SoC that were similar for demographic and clinical data. We evaluated changes in hypoxemia and inflammatory markers at admission (Day 0) and after 5 days of treatment (Day 5) and the clinical course of the disease. From Day 0 to Day 5, the ratio of arterial oxygen partial pressure to fractional inspired oxygen (P/F) increased from 222 ± 62 to 274 ± 97 (p < 0.0001) in the remdesivir group and decreased from 223 ± 62 to 183 ± 76 (p < 0.05) in the SoC group. Interleukine-6 levels decreased in the remdesivir (45.9 to 17.5 pg/mL, p < 0.05) but not in the SoC group. Remdesivir reduced the need for ventilatory support and the length of hospitalization. In conclusion, compared to standard care, remdesivir rapidly improves hypoxia and inflammation, causing a better course of the disease in moderate to severe COVID-19.
Subject(s)
COVID-19 , Humans , COVID-19/complications , SARS-CoV-2 , Retrospective Studies , Treatment Outcome , COVID-19 Drug Treatment , Antiviral Agents/therapeutic use , Hypoxia/drug therapy , OxygenABSTRACT
OBJECTIVES: To investigate relationships between histogram-based high-resolution CT (HRCT) indexes and pulmonary function tests (PFTs) in interstitial lung diseases. METHODS: Forty-nine patients having baseline and 1-year HRCT examinations and PFTs were investigated. Histogram-based HRCT indexes were calculated; strength of associations with PFTs was investigated using Pearson correlation. Patients were divided into progressive and non-progressive groups. HRCT indexes were compared between the two groups using the U-test; within each group, baseline and follow-up Wilcoxon analysis was performed. Receiver operating characteristic analysis was used for predicting disease progression. RESULTS: At baseline, moderate correlations were observed considering kurtosis and diffusion capacity of the lungs for carbon monoxide (DLCO) (r = 0.54) and skewness and DLCO (r = 0.559), whereas weak but significant correlations were observed between forced vital capacity and kurtosis (r = 0.368, p = 0.009) and forced vital capacity and skewness (r = 0.391, p = 0.005). Negative correlations were reported between HAA% and PFTs (from r = -0.418 up to r = -0.507). At follow-up correlations between quantitative indexes and PFTs were also moderate, except for high attenuation area (HAA)% -700 and DLCO (r = -0.397). In progressive subgroup, moderate and strong correlations were found between DLCO and HRCT indexes (r = 0.595 kurtosis, r = 0.672 skewness, r=-0. 598 HAA% -600 and r = -0.626 HAA% -700). At follow-up, we observed significant differences between the two groups for kurtosis (p = 0.029), HAA% -600 (p = 0.04) and HAA% -700 (p = 0.02). To predict progression, ROC analysis reported sensitivity of 90.9% and specificity of 51.9% using a threshold value of δ kurtosis <0.03. CONCLUSION: At one year, moderate correlations suggest that progression could be assessed through HRCT quantification. ADVANCES IN KNOWLEDGE: This study promotes histogram-based HRCT indexes in the assessment of progressive pulmonary fibrosis.
Subject(s)
Lung Diseases, Interstitial , Pulmonary Fibrosis , Humans , Pulmonary Fibrosis/diagnostic imaging , Retrospective Studies , Lung/diagnostic imaging , Lung Diseases, Interstitial/diagnostic imaging , Vital CapacityABSTRACT
Mixed Connective Tissue Disease (MCTD) is an autoimmune disease first described by Sharp et al in 1972, characterized by the presence of anti-Ribonucleoprotein antibodies directed against the U1 complex (anti-U1RNP). The condition shares clinical characteristics with Systemic Lupus Erythematosus, Rheumatoid Arthritis, and Systemic Sclerosis. Diagnosis is quite difficult due to its rarity, the lack of validated classification criteria, and its heterogeneous clinical presentation. While in the early stages its nuanced clinical features might lead to it being incorrectly classified as other Connective Tissue Diseases (CTDs) or even not recognized, in cases of longstanding disease its classification as a CTD is clear but challenging to discriminate from overlap syndromes. MCTD should be considered a distinct entity due to the presence of a specific genetic substrate and the presence of the high titer of a specific autoantibody, anti-U1RNP, present in all the commercial kits for Extractable Nuclear Antigens, and almost always associated with Antinuclear Antibody positivity with a coarse speckled pattern. Except for anti-U1RNP, no specific biomarkers are available to guide clinicians to a correct classification of MCTD, which is arrived at by the association of clinical, serological and instrumental evaluation. In the first stages, the disease is mainly characterized by Raynaud's phenomenon, inflammatory arthritis, puffy fingers, myalgia and/or myositis, and rarely, trigeminal neuropathy. Longstanding disease is generally associated with the development of Pulmonary Hypertension and Interstitial Lung Disease, which are the two main causes of mortality in MCTD. The aim of this review is to summarize current knowledge on the early recognition of MCTD.
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Perinuclear Anti Neutrophil Cytoplasmic Antibody (p-ANCA) is a serological marker of Microscopic Polyangiitis (MPA), a vasculitis associated with lung involvement potentially mimicking Idiopathic Pulmonary Fibrosis (IPF). In this study, we evaluated the role of p-ANCA in predicting clinical evolution and prognosis in a cohort of IPF patients. In this observational, retrospective, case-control study, we compared 18 patients with an IPF diagnosis and p-ANCA positivity with 36 patients with seronegative IPF, matched for age and sex. IPF patients with and without p-ANCA showed similar lung function decline during the follow-up, but IPF p-ANCA+ showed better survival. Half of IPF p-ANCA+ patients were classified as MPA for the development of renal involvement (55%) or skin signs (45%). The progression towards MPA was associated with high levels of Rheumatoid Factor (RF) at baseline. In conclusion, p-ANCA, mainly when associated with RF, could predict the evolution of Usual Interstitial Pneumonia (UIP) towards a definite vasculitis in patients, with a better prognosis compared with IPF. In this view, ANCA testing should be included in the diagnostic workup of UIP patients.
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Lung involvement, especially interstitial lung disease, is a potentially severe extra-glandular manifestation of Primary Sjogren's Syndrome (pSS-ILD). ILD can manifest either as a late complication of pSS or anticipate sicca symptoms, likely reflecting two different patho-physiological entities. Presence of lung involvement in pSS subjects can remain subclinical for a long time; therefore, patients should be actively screened, and lung ultrasound is currently being investigated as a potential low cost, radiation-free, easily repeatable screening tool for detection of ILD. In contrast, rheumatologic evaluation, serology testing, and minor salivary gland biopsy are crucial for the recognition of pSS in apparently idiopathic ILD patients. Whether the HRCT pattern influences prognosis and treatment response in pSS-ILD is not clear; a UIP pattern associated with a worse prognosis in some studies, but not in others. Many aspects of pSS-ILD, including its actual prevalence, association with specific clinical-serological characteristics, and prognosis, are still debated by the current literature, likely due to poor phenotypic stratification of patients in clinical studies. In the present review, we critically discuss these and other clinically relevant "hot topics" in pSS-ILD. More specifically, after a focused discussion, we compiled a list of questions regarding pSS-ILD that, in our opinion, are not easily answered by the available literature. We subsequently tried to formulate adequate answers on the basis of an extensive literature search and our clinical experience. At the same, we highlighted different issues that require further investigation.
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BACKGROUND: Connective tissue diseases (CTDs) are responsible for about 20% of interstitial lung disease (ILD) cases, but their diagnosis in a pulmonary unit (PU) is not always straightforward due to a heterogeneous clinical picture. OBJECTIVES: The aim of this study was to evaluate the clinical presentation of rheumatoid arthritis (RA) and CTD-ILD cases diagnosed in PU, compared to RA and CTD patients diagnosed in a rheumatologic unit (RU). METHODS: Patients with RA, systemic sclerosis (SSc), primary SjÓ§gren's syndrome (pSS), and idiopathic inflammatory myopathy were retrospectively enrolled from an RU and a PU designated to manage ILD during a period from January 2017 to October 2022. The classification of CTD-PU was carried out in a multidisciplinary setting, including the same rheumatologists that diagnosed CTD in the RU. RESULTS: ILD-CTD-PU patients were prevalently male and older. Progression from undifferentiated CTD to a specific condition was more common in ILD-CTD-PU, and those patients generally obtained a lower score on specific classification criteria. RA-PU patients resembled polymyalgia rheumatica in 47.6% of cases, also showing a greater proportion of typical joint deformities (p = 0.02). SSc-PU patients showed a usual interstitial pneumonia pattern in 76% of cases and, compared with SSc-RU, were more commonly seronegative (p = 0.03) and generally lacked fingertip lesions (p = 0.02). The majority of the diagnoses of pSS-PU were in patients with previously diagnosed ILD, in which seropositivity and sicca syndrome developed during follow-up. CONCLUSIONS: CTD-ILD patients diagnosed in the PU show severe lung involvement and a nuanced autoimmune clinical picture.
Subject(s)
Arthritis, Rheumatoid , Connective Tissue Diseases , Lung Diseases, Interstitial , Scleroderma, Systemic , Humans , Male , Retrospective Studies , Prognosis , Lung Diseases, Interstitial/complications , Lung Diseases, Interstitial/diagnosis , Connective Tissue Diseases/complications , Lung , Scleroderma, Systemic/complicationsABSTRACT
Over the last three years, after the outbreak of the COVID-19 pandemic, an unprecedented number of novel diagnostic tests have been developed. Assays to evaluate the immune response to SARS-CoV-2 have been widely considered as part of the control strategy. The lateral flow immunoassay (LFIA), to detect both IgM and IgG against SARS-CoV-2, has been widely studied as a point-of-care (POC) test. Compared to laboratory tests, LFIAs are faster, cheaper and user-friendly, thus available also in areas with low economic resources. Soon after the onset of the pandemic, numerous kits for rapid antibody detection were put on the market with an emergency use authorization. However, since then, scientists have tried to better define the accuracy of these tests and their usefulness in different contexts. In fact, while during the first phase of the pandemic LFIAs for antibody detection were auxiliary to molecular tests for the diagnosis of COVID-19, successively these tests became a tool of seroprevalence surveillance to address infection control policies. When in 2021 a massive vaccination campaign was implemented worldwide, the interest in LFIA reemerged due to the need to establish the extent and the longevity of immunization in the vaccinated population and to establish priorities to guide health policies in low-income countries with limited access to vaccines. Here, we summarize the accuracy, the advantages and limits of LFIAs as POC tests for antibody detection, highlighting the efforts that have been made to improve this technology over the last few years.
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Fibromyalgia (FM) is a common rheumatologic disorder characterised by widespread muscular pain. Myalgia is also a common clinical feature in Connective Tissue Disease (CTD), and FM should be studied for the concomitant presence of a CTD. The aim of this study is to evaluate the prevalence of Myositis-Specific and Myositis-Associated Antibodies (MSA/MAA) in a cohort of FM patients. We enrolled 233 consecutive FM patients (defined according to the 2016 criteria) that did not report clinical signs of autoimmune disorders and followed them for at least one year. The patients were tested for MSA/MAA with immunoblotting. FM patients were seropositive for Antinuclear Antibodies (ANA) in 24% of cases, for MSA in 9%, and for MAA in 6%. A specific diagnosis of CTD was made in 12 patients (5.2%), namely, 5 cases of primary Sjögren's Syndrome and 7 of Idiopathic Inflammatory Myopathy. Seropositive patients showed clinical features similar to those who were seronegative at baseline. A CTD diagnosis was associated with ANA positivity (p = 0.03, X2 4.9), the presence of a speckled pattern (p = 0.02, X2 5.3), positivity for MAA (p = 0.004, X2 8.1), and MSA (p = 0.003, X2 9.2). In conclusion, a non-negligible proportion of FM patients may be seropositive for MSA/MAA, and that seropositivity might suggest a diagnosis of CTD.
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In recent decades, several pieces of evidence have drawn greater attention to the topic of innate immunity, in particular, interferon (IFN) and Interleukin 6 in the pathogenesis of idiopathic inflammatory myopathies (IIM). Both of these molecules transduce their signal through a receptor coupled with Janus kinases (JAK)/signal transducer and activator of transcription proteins (STAT). In this review, we discuss the role of the JAK/STAT pathway in IIM, evaluate a possible therapeutic role for JAK inhibitors in this group of diseases, focusing on those with the strongest IFN signature (dermatomyositis and antisynthetase syndrome).
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PURPOSE: The coexistence of obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) is known as "overlap syndrome" (OS). Patients with OS are usually older than patients with OSA alone, suffer from more profound oxygen desaturation during the obstructive events often accompanied by sustained nocturnal hypoventilation. Although oxygen-enriched positive airway pressure (PAP) is the treatment of choice in these patients, this therapy is often poorly tolerated particularly by the elderly. The aim of this study was to assess the usefulness of nocturnal oxygen therapy via nasal high flow (NHF-OT) as a possible alternative to PAP in patients with OS. METHODS: Patients > 65 years old with OS and nocturnal respiratory failure (time spent below SaO2 90% (T90) > 30%) had cardio-respiratory monitoring performed at baseline, during NHF-OT, or during conventional oxygen therapy (COT). RESULTS: A total of 40 patients were enrolled in the study. NHF-OT significantly reduced the apnea-hypopnea index (AHI) in all patients compared to baseline and COT. The mean basal AHI was 25.4 ± 8.6. During COT and NHF-OT, the AHI was 19.4 ± 7 and 5.4 ± 4.6, respectively (P < 0.001) and 19 patients reached an AHI < 5 during NHF-OT. The mean nocturnal SaO2% was 86.2 ± 2.6 at baseline and at equivalent FiO2 it significantly increased to 91.8 ± 2.4 during COT and to 93.9 ± 2.5 during NHF-OT (P < 0.001). The T90% was 48.7 ± 20.1 at baseline, 16.8 ± 11.7 during COT, and 8.8 ± 8.0 during NHF-OT (P < 0.001). CONCLUSIONS: In elderly patients with OS, nocturnal treatment with NHF-OT significantly reduces obstructive episodes and improves oxygenation. As the treatment is generally well tolerated compared to PAP, NHF-OT may be a possible alternative therapy in this subgroup of patients.
Subject(s)
Pulmonary Disease, Chronic Obstructive , Sleep Apnea, Obstructive , Humans , Aged , Oxygen , Pulmonary Disease, Chronic Obstructive/complications , Oxygen Inhalation Therapy , Lung , SyndromeABSTRACT
OBJECTIVES: To evaluate the rate of progression towards specific autoimmune diseases (SADs) of a prospective, multi-centre cohort of patients classifiable as interstitial pneumonia with autoimmune features (IPAF). METHODS: IPAF patients were enrolled based on specific research criteria, and jointly followed by rheumatologists and pulmonologists for at least one year with clinical check-ups, serological exams including autoimmunity, capillaroscopy and high-resolution computed tomography (HRCT). Diagnostic assessment was repeated at least once a year, or earlier when deemed useful. RESULTS: We enrolled 191 IPAF patients through 95 different combinations of IPAF criteria. Of these, 24.1% progressed towards SAD, mainly in connective tissue diseases but also in microscopic polyangiitis. The IPAF patients who progressed were younger than stable IPAF patients (63±10 years vs. 68±9 years, p=0.002) and had a longer follow-up (36.9±18.7 vs. 29.3±15.7 months, p=0.007), but similar severity. No parameters were associated with overall progression, but some parameters were associated with the development of specific diagnoses: Sjögren's syndrome with positivity for SSA (p=0.007, χ2 7.4); idiopathic inflammatory myopathy with mechanic's hands (p=<0.0001, χ2 12.6), organizing pneumonia pattern (p=0.01, χ2 6.1), positivity for anti-Pm/scl (p=0.04 χ2 4.1) and anti-MDA5 (p=0.04, χ2 4.2); systemic sclerosis with palmar telangiectasias (p=<0.0001 2 18.3), positivity for anti-Scl70 (p=<0.0001 χ2 12.5) and anti-PM/Scl (p=0.001 χ2 10.1). CONCLUSIONS: IPAF patients had a rate of progression towards SAD similar to that reported in previous studies on undifferentiated connective tissue diseases, thus including some patients in which lung involvement could represent the first or even the sole clinical manifestation of a SAD.