Lung adenocarcinoma discovered during the follow-up of lung-dominant connective tissue disease: a case report and literature review.

Interstitial lung disease (ILD) can lead to lung cancer, which brings great challenges to differential diagnosis and comprehensive treatment. However, the clinical features of lung-dominant connective tissue disease (LD-CTD) related ILD combined with lung cancer has not been validated. We report the case of an 80-year-old woman with LD-CTD treated regularly with nintedanib who presented progressive dyspnoea and hypoxemia after recurrent viral infections. Her chest computed tomography (CT) showed aggravated interstitial fibrosis in both lower lungs with moderate right pleural effusion. Clinicians should be alert to lung cancer in patients who are experiencing poor responsiveness to treatment or acute progression of ILD. The available literatures about the differential diagnosis of clinical manifestations, imaging, treatment and prognosis of LD-CTD are reviewed and discussed in this study.

Identification of connective tissue disease autoantibodies and a novel autoantibody anti-annexin A11 in patients with "idiopathic" interstitial lung disease.

BACKGROUND: Autoantibodies are a hallmark feature of Connective Tissue Diseases (CTD). Their presence in patients with idiopathic interstitial lung disease (ILD) may suggest covert CTD. We aimed to determine the prevalence of CTD autoantibodies in patients diagnosed with idiopathic ILD. METHODS: 499 patient sera were analysed: 251 idiopathic pulmonary fibrosis (IPF), 206 idiopathic non-specific interstitial pneumonia (iNSIP) and 42 cryptogenic organising pneumonia (COP). Autoantibody status was determined by immunoprecipitation. RESULTS: 2.4% of IPF sera had a CTD-autoantibody compared to 10.2% of iNSIP and 7.3% of COP. 45% of autoantibodies were anti-synthetases. A novel autoantibody targeting an unknown 56 kDa protein was found in seven IPF patients (2.8%) and two NSIP (1%) patients. This was characterised as anti-annexin A11. CONCLUSION: Specific guidance on autoantibody testing and interpretation in patients with ILD could improve diagnostic accuracy. Further work is required to determine the clinical significance of anti-annexin A11.

Relationship between idiopathic interstitial pneumonias (IIPs) and connective tissue disease-related interstitial lung disease (CTD-ILD): A narrative review.

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.

Clinical characteristics of patients with connective tissue disease-related interstitial lung disease: a retrospective analysis.

INTRODUCTION: Interstitial lung disease is one of the most critical manifestations of connective tissue diseases that may cause morbidity and mortality. This study aimed to evaluate the clinical and demographic characteristics and treatment of the patients with connective tissue disease-related interstitial lung disease. METHOD: This retrospective observational study included patients from the Gulhane Rheumatology Interstitial Lung Disease cohort between October 2016 and June 2023. The patients were assessed retrospectively. RESULTS: A total of 173 patients were included in the study with a mean age of 63.4 ± 11.9 years. The frequencies of CTD were 34.1% Sjogren's syndrome, 30.1% rheumatoid arthritis, 25.4% systemic sclerosis, 5.8% undifferentiated connective tissue disease, 2.9% idiopathic inflammatory myositis, 1.2% mixt connective tissue disease, and 0.6% systemic lupus erythematosus in decreasing frequencies. Nonspecific interstitial pneumonia, which was the most common interstitial lung disease pattern in 103 (59.5%) patients, was most frequent among patients with SS and SSc (p < 0.001 vs. p < 0.001). Usual interstitial pneumonia was most frequent among patients with RA (p < 0.001). All patients received immunosuppressive treatment, most commonly azathioprine. 57.2% were using immunosuppressives for ILD. Six patients had mortality, and infections were the leading cause. CONCLUSIONS: As a critical manifestation of connective tissue diseases, immunosuppressive treatment is indispensable in the management of interstitial lung diseases especially those at an increased risk for progression. The treatment approaches should be assessed in a patient-based way. The patients under immunosuppressive treatment should be cautiously followed for infections. Key Points • Interstitial lung disease is a noteworthy manifestation of connective tissue diseases. • The clinical findings, treatment requirements, and progression vary according to the severity of the disease. • Immunosuppressive treatment may be essential in patients with worsening symptoms, impaired pulmonary function tests, and radiological findings.

Connective tissue disease-associated interstitial lung disease.

Connective tissue disease-associated interstitial lung disease (CTD-ILD) represents a group of systemic autoimmune disorders characterized by immune-mediated organ dysfunction. Systemic sclerosis, rheumatoid arthritis, idiopathic inflammatory myositis, and Sjögren's syndrome are the most common CTDs that present with pulmonary involvement, as well as with interstitial pneumonia with autoimmune features. The frequency of CTD-ILD varies according to the type of CTD, but the overall incidence is 15%, causing an important impact on morbidity and mortality. The decision of which CTD patient should be investigated for ILD is unclear for many CTDs. Besides that, the clinical spectrum can range from asymptomatic findings on imaging to respiratory failure and death. A significant proportion of patients will present with a more severe and progressive disease, and, for those, immunosuppression with corticosteroids and cytotoxic medications are the mainstay of pharmacological treatment. In this review, we summarized the approach to diagnosis and treatment of CTD-ILD, highlighting recent advances in therapeutics for the various forms of CTD.

Cutis verticis gyrata associated with congenital heart disease.

Cutis verticis gyrata (CVG) is a very rare benign disorder characterised by convoluted folds and deep furrows of the scalp that mimic cerebral sulci and gyri. Associations with other pathologies as neuropsychiatric and/or ophthalmologic disorders, secondary cases to inflammatory or neoplastic processes, as well as cases associated to genetic disorders as Turner's syndrome have been reported, but there is no literature describing an association with a congenital structural heart defect and no other underlying condition. We report a case of primary CVG in a 3-week-old female infant associated with an echocardiographic diagnosis of cor triatriatum. Other systemic examination findings and investigations were unremarkable, and the patient has normal neurodevelopment at 1 year old. Aside from the neuropsychiatric and ophthalmologic pathologies commonly associated with primary non-essential CVG, it should be noted that isolated congenital cardiac lesions are also possible, so as to increase our index of suspicion in patients with the disorder.

Diagnosis and treatment of cardiovascular disease in patients with heritable connective tissue disorders or heritable thoracic aortic diseases.

Patients with heritable connective tissue disorders (HCTDs), represented by Marfan syndrome, can develop fatal aortic and/or arterial complications before age 50. Therefore, accurate diagnosis, appropriate medical treatment, and early prophylactic surgical treatment of aortic and arterial lesions are essential to improve prognosis. Patients with HCTDs generally present with specific physical features due to connective tissue abnormalities, while some patients with heritable thoracic aortic diseases (HTADs) have few distinctive physical characteristics. The development of genetic testing has made it possible to provide accurate diagnoses for patients with HCTDs/HTADs. This review provides an overview of the diagnosis and treatment of HCTDs/HTADs, including current evidence on cardiovascular interventions for this population.

Histopathological significance of connective tissue disease-associated interstitial lung disease in transbronchial lung cryobiopsy specimens.

Differentiating between idiopathic interstitial pneumonia (IIP) and secondary interstitial pneumonia, particularly connective tissue disease-associated interstitial lung disease (CTD-ILD), can be challenging histopathologically, and there may be discrepancies among pathologists. While surgical lung biopsy has traditionally been considered the gold standard for diagnosing interstitial pneumonia, the usefulness of transbronchial lung cryobiopsy (TBLC) has been reported. If TBLC could effectively distinguish between primary and secondary diseases, it would provide a less invasive option for patients. The aim of this study was to identify specific pathologic findings in TBLC specimens that could assist in distinguishing CTD-ILD from IIP. A total of 93 underwent TBLC at Tenri Hospital between 2018 and 2022. We retrospectively reviewed cases of CTD-ILD exhibiting a nonspecific interstitial pneumonia (NSIP) pattern (CTD-NSIP) and cases of NSIP with an unknown etiology (NSIP-UE), as determined through multidisciplinary discussion. Nineteen patients with CTD-NSIP and 26 patients with NSIP-UE were included in the study for clinicopathological analysis. The CTD-NSIP group had a significantly higher proportion of female patients compared to the NSIP-UE group (79% vs. 31%; p = 0.002). The presence of both fresh and old intraluminal fibrosis within the same TBLC specimen was significantly more frequent in CTD-NSIP group than in the NSIP-UE group (p = 0.023). The presence of an NSIP pattern with co-existing fresh and old intraluminal fibrosis in TBLC specimens raised suspicion for CTD-ILD.

Pulmonary hypertension in connective tissue diseases: What every CTD specialist should know - but is afraid to ask!

Pulmonary hypertension (PH) is a possible complication of connective tissue diseases (CTDs), especially systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). It is defined by an elevation of the mean pulmonary arterial pressure above 20mmHg documented during a right heart catheterization (RHC). Due to their multiorgan involvement, CTDs can induce PH by several mechanisms, that are sometimes intricated: pulmonary vasculopathy (group 1) affecting arterioles (pulmonary arterial hypertension, PAH) and possibly venules (pulmonary veno-occlusive-like disease), left-heart disease (group 2), chronic lung disease (group 3) and/or chronic thromboembolic PH (group 4). PH suspicion is often raised by clinical manifestations (dyspnea, fatigue), echocardiographic data (increased peak tricuspid regurgitation velocity), isolated decrease in DLCO in pulmonary function tests, and/or unexplained elevation of BNP/NT-proBNP. Its formal diagnosis always requires a hemodynamic confirmation by RHC. Strategies for PH screening and RHC referral have been extensively investigated for SSc-PAH but data are lacking in other CTDs. Therapeutic management of PH depends of the underlying mechanism(s): PAH-approved therapies in group 1 PH (with possible use of immunosuppressants, especially in case of SLE or MCTD); management of an underlying left-heart disease in group 2 PH; management of an underlying chronic lung disease in group 3 PH; anticoagulation, pulmonary endartectomy, PAH-approved therapies and/or balloon pulmonary angioplasty in group 4 PH. Regular follow-up is mandatory in all CTD-PH patients.

[Update in interstitial lung disease 2023].

The notable advances in interstitial lung disease (ILD) published in Chinese and international authoritative journals from November 2022 to October 2023 were systematically reviewed in our annual review. The year 2023 brought significant advances about mechanism, diagnosis and treatment of idiopathic pulmonary fibrosis, connective tissue diseases associated ILD, sarcoidosis, progressive pulmonary fibrosis and rare ILDs. The related global and/or Chinese commentaries and guidelines were also reviewed in our paper. We also highlighted the important findings of epidemiologic and health economic data on idiopathic pulmonary fibrosis and sarcoidosis.

The predictive value of antinuclear antibodies in patients with suspected connective tissue disease for the development of connective tissue diseases.

OBJECTIVES: Early confirmation of the diagnosis of connective tissue diseases (CTD) is important, as prolonged disease activity can result in irreversible organ damage. Although antinuclear antibodies (ANAs) have been shown to precede the diagnosis of SLE, this has not been investigated in large cohorts for other CTDs. In this study, we investigated whether the presence of antinuclear autoantibodies in undiagnosed patients suspected of having CTDs is predictive of development of a future CTD. METHODS: We screened the Electronic Health Records of a cohort of 1030 patients, who were tested for ANAs and their specificity in 2013/2014, to evaluate whether new CTD diagnoses had been recorded by a clinician between the original blood draw date and 2020. We compared the prevalence of ANAs in patients who developed a new CTD diagnosis during follow-up with patients with similar symptoms at baseline who did not receive a subsequent CTD diagnosis and with patients with an established CTD at baseline. RESULTS: Sixteen out of 1030 patients had developed a new CTD in the studied time period. The mean time period between baseline blood draw and subsequent CTD diagnosis of these patients was approximately 2.3 years. Eleven out of 16 (69%) newly diagnosed patients had positive ANA screening tests, compared to 54% of patients with a CTD diagnosis at baseline (p=ns) and 30% of symptomatic undiagnosed patients (p<0.001). This resulted in a positive predictive value (PPV) of 7% and a negative predictive value (NPV) of 98% for the development of a new CTD in undiagnosed symptomatic patients. For specific ANAs associated with the suspected CTD, the PPV was 12%, with a NPV of 98%. CONCLUSIONS: Progression to a CTD diagnosis is rare in undiagnosed patients. Undiagnosed patients with symptoms associated with a CTD who progress to a CTD more often have ANAs than patients with similar symptoms who do not progress to a CTD. ANA testing can be used to more stringently select patients who should remain in follow-up.

Prognostic analysis of pulmonary hypertension with lung parenchymal lesion: Comparison of mortality with and without connective tissue disease.

BACKGROUND: The prognosis of pulmonary hypertension (PH) associated with connective tissue diseases related to interstitial pneumonia (CTD-IP PH) is relatively good among patients with PH and lung disease. However, the impact of pulmonary vasodilator treatment on the prognosis of CTD-IP PH compared with that of PH-induced chronic lung disease (group-3 PH) remains unclear. METHODS: From 2012 to 2022, 50 patients with lung parenchymal lesions diagnosed with PH (mean pulmonary arterial pressure >20 mmHg) at Juntendo University Hospital were divided into two groups: CTD-IP PH (30 patients) and group 3-PH (20 patients). The impact of pulmonary vasodilator treatment and the use of long-term oxygen therapy (LTOT) on the prognosis of each group was examined retrospectively. RESULTS: The prognosis of CTD-IP PH was significantly better compared to group-3 PH. While the treatment with pulmonary vasodilators did not affect the prognosis in group 3-PH, the prognosis of the patients treated with vasodilators in the CTD-IP PH group was significantly better than that of the non-treated patients. Treatment with multi-pulmonary vasodilators did not affect the prognosis in CTD-IP PH. Although the prognosis for the patients with LTOT was poor in all registered patients in the present study, treatment with pulmonary vasodilators improved the prognosis even under the use of LTOT in CTD-IP PH (P = 0.002). In a multivariate analysis of the CTD-IP PH group, pulmonary vasodilator treatment was an independent factor for better prognosis. CONCLUSION: Treatment with a pulmonary vasodilator for CTD-IP PH may improve the prognosis, even in patients requiring LTOT.

Flemish network on rare connective tissue diseases (CTD): patient pathways in systemic sclerosis. First steps taken.

Despite the low prevalence of each rare disease, the total burden is high. Patients with rare diseases encounter numerous barriers, including delayed diagnosis and limited access to high-quality treatments. In order to tackle these challenges, the European Commission launched the European Reference Networks (ERNs), cross-border networks of healthcare providers and patients representatives. In parallel, the aims and structure of these ERNs were translated at the federal and regional levels, resulting in the creation of the Flemish Network of Rare Diseases. In line with the mission of the ERNs and to ensure equal access to care, we describe as first patient pathways for systemic sclerosis (SSc), as a pilot model for other rare connective and musculoskeletal diseases. Consensus was reached on following key messages: 1. Patients with SSc should have multidisciplinary clinical and investigational evaluations in a tertiary reference expert centre at baseline, and subsequently every three to 5 years. Intermediately, a yearly clinical evaluation should be provided in the reference centre, whilst SSc technical evaluations are permissionably executed in a centre that follows SSc-specific clinical practice guidelines. In between, monitoring can take place in secondary care units, under the condition that qualitative examinations and care including interactive multidisciplinary consultations can be provided. 2. Patients with early diffuse cutaneous SSc, (progressive) interstitial lung disease and/or pulmonary arterial hypertension should undergo regular evaluations in specialised tertiary care reference institutions. 3. Monitoring of patients with progressive interstitial lung disease and/or pulmonary (arterial) hypertension will be done in agreement with experts of ERN LUNG.

Characteristics and risk factors of interstitial pneumonia with autoimmune features.

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. CONCLUSION: 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.

Multiocular defect in the Old English Sheepdog: A canine form of Stickler syndrome type II associated with a missense variant in the collagen-type gene COL11A1.

Multiocular defect has been described in different canine breeds, including the Old English Sheepdog. Affected dogs typically present with multiple and various ocular abnormalities. We carried out whole genome sequencing on an Old English Sheepdog that had been diagnosed with hereditary cataracts at the age of five and then referred to a board-certified veterinary ophthalmologist due to owner-reported visual deterioration. An ophthalmic assessment revealed that there was bilateral vitreal degeneration, macrophthalmos, and spherophakia in addition to cataracts. Follow-up consultations revealed cataract progression, retinal detachment, uveitis and secondary glaucoma. Whole genome sequence filtered variants private to the case, shared with another Old English Sheepdog genome and predicted to be deleterious were genotyped in an initial cohort of six Old English Sheepdogs (three affected by multiocular defect and three control dogs without evidence of inherited eye disease). Only one of the twenty-two variants segregated correctly with multiocular defect. The variant is a single nucleotide substitution, located in the collagen-type gene COL11A1, c.1775T>C, that causes an amino acid change, p.Phe1592Ser. Genotyping of an additional 14 Old English Sheepdogs affected by multiocular defect revealed a dominant mode of inheritance with four cases heterozygous for the variant. Further genotyping of hereditary cataract-affected Old English Sheepdogs revealed segregation of the variant in eight out of nine dogs. In humans, variants in the COL11A1 gene are associated with Stickler syndrome type II, also dominantly inherited.

[Depressive and anxiety symptoms in hereditary connective tissue disorders : case description and systematic literature review]. / Depressieve en angstklachten bij erfelijke bindweefselaandoeningen: casus en systematisch literatuuroverzicht.

Hereditary connective tissue disorders are a broad group of congenital disorders that are characterized by a pathological weakness of the connective tissue as a result of an incorrect genesis, leading to multisystem complaints. We describe a 14-year-old patient with the hereditary connective tissue disorder Loeys-Dietz syndrome who was admitted to a child psychiatric crisis unit because of depressive and anxiety symptoms. A systematic literature search was carried out to analyze the prevalence of depressive and anxiety symptoms in individuals with hereditary connective tissue disorders Loeys-Dietz syndrome, Ehlers-Danlos syndrome and Marfan syndrome, to identify a possible association between these disorders and explanations for this. We conclude that there is an increased incidence of depression and anxiety symptoms in which pain, fatigue, social support and functioning, quality of life and functional limitations seem to play a role. There is a need for further research to determine exactly which factors contribute and how these can be targeted in prevention and treatment.

Primary Epiploic Appendagitis: A Mimicker of Abdominal Pain.

Epiploic appendagitis is a rare cause of acute lower abdominal pain. Epiploic appendices are fat-filled serosal outpouchings of the cecum and sigmoid colon. Primary epiploic appendagitis (PEA) is characterized by epiploic inflammation caused by torsion of the appendage leading to ischemia or thrombosis of the appendage draining vein. Secondary epiploic appendagitis occurs in association with other inflammatory conditions of the abdomen or pelvis, most commonly diverticulitis. PEA is an important clinical mimicker of more severe causes of acute abdominal pain, such as diverticulitis, appendicitis, or gynaecological causes. The ease of access to computed tomography (CT), the diagnostic test of choice, has resulted in increased recognition of PEA. The classic CT findings of PEA are an ovoid mass measuring between 1.5 and 3.5 cm surrounded by a hyperattenuating/hyperdense ring with a centrally located hyperdense area. It is important to diagnose PEA as it is self-limiting and the correct diagnosis can prevent unnecessary hospital admission, antibiotic use, or even surgical intervention. We present a case of a 65-year-old male with a history of diverticulitis, presenting with left lower quadrant abdominal pain who was diagnosed with PEA based on CT and successfully managed with conservative treatment.