Introduction: A study was conducted to determine whether the human leukocyte antigen (HLA) B alleles are implicated in the susceptibility to Henoch-Schönlein purpura (HSP) in the largest series of Caucasian HSP patients ever assessed for genetic studies. Methods: The study population was composed of 349 Spanish patients diagnosed with HSP fulfilling the American College of Rheumatology and the Michel et al. classification criteria, and 335 sex and ethnically matched controls. HLA-B phenotypes were determined by sequencing-based typing (SBT) and analyzed by chi-square or Fisher exact test. Results: A statistically significant increase of HLA-B*41:02 allele in HSP patients when compared with controls was found (8.3% versus 1.5% respectively; P = 0.0001; OR (odds ratio) =5.76 [2.15-19.3]). These results remained statistically significant after adjusting for Bonferroni correction (P = 0.0028). An internal validation also confirmed the susceptibility effect on HSP associated with HLA-B*41:02 (OR = 5.70 [1.98-16.44]). Since a former study described an association between HLA-DRB1*01:03 and HSP susceptibility, we also evaluated the implication of HLA-B*41:02 independently of HLA-DRB1*01:03. Interestingly, the association remained statistically significant (P = 0.0004, OR = 4.97 [1.8-16.9]). No HLA-B association with specific HSP clinical features was found. Conclusions: Our study indicates that HLA-B*41:02 is associated with the susceptibility to HSP in Spanish patients irrespective of HLA-DRB1 status.

The aim of this study was to determine the role of endothelin-1 (ET-1), a molecule involved in multiple vascular and fibrosing abnormalities, as a biomarker of interstitial lung disease (ILD), as well as its use for the differential diagnosis between idiopathic pulmonary fibrosis (IPF) and ILD associated with autoimmune diseases (AD-ILD), using a large and well-defined cohort of patients with ILD. A total of 112 patients with IPF, 91 patients with AD-ILD (28 rheumatoid arthritis (RA), 26 systemic sclerosis, 20 idiopathic inflammatory myositis and 17 interstitial pneumonia with autoimmune features) and 44 healthy controls were included. ET-1 serum levels were determined by enzyme-linked immunosorbent assay. A significant increase in ET-1 levels was found in patients with IPF compared to controls. Likewise, AD-ILD patients also showed higher ET-1 levels than controls when the whole cohort was stratified by the type of AD. Similar ET-1 levels were found in IPF and AD-ILD patients, regardless of the underlying AD. Interestingly, increased ET-1 levels were correlated with worse lung function in IPF and RA-ILD patients. Our study supports that serum ET-1 may be useful as a biomarker of ILD, although it could not help in the differential diagnosis between IPF and AD-ILD. Moreover, ET-1 levels may be associated with ILD severity.

Interstitial lung disease (ILD) may occur in patients with a rheumatic autoimmune disease (AD), increasing their risk of morbidity and mortality. However, little is known about the prevalence of AD in patients diagnosed with an ILD. In this prospective study, we determined the spectrum of ILD associated with AD (AD-ILD) among patients sent for assessment to a single clinic of ILD and lung transplantation from a referral center between May 2016 and December 2019. ILD diagnosis was made by pneumologists based on clinical and radiological findings and pulmonary function test abnormalities. All patients with ILD were also assessed by experienced rheumatologists. During the period of assessment, 338 patients were diagnosed with ILD. Among them, 32.8% fulfilled definitions for an AD. Most cases with AD-ILD had a diagnosis of rheumatoid arthritis (27.0%), systemic sclerosis (26.1%) or anti-synthetase syndrome (17.1%). Interestingly, 18% of the patients with AD-ILD were diagnosed as having an interstitial pneumonia with autoimmune features. Antinuclear antibodies and non-specific interstitial pneumonia were the most frequent positive autoantibodies and radiological pattern found in AD-ILD patients, respectively. In conclusion, our study indicates that a high number of ILD patients have a related AD. Consequently, close collaboration among rheumatologists and pneumologists is needed.

In the present study, we aimed to report our experience with rituximab (RTX) in the treatment of patients with ILD associated with AD (AD-ILD) at a single center. For this purpose, clinical characteristics, radiological findings, and pulmonary function tests (PFTs) of RTX-treated AD-ILD-patients seen from May 2016 until March 2020 at a referral center for individuals with ILD were retrospectively reviewed. Additionally, an updated literature review was conducted. A total of 26 patients (mean age 58.3 ± 11.1 years at ILD diagnosis) was included. The most common ADs related to ILD were systemic sclerosis, idiopathic inflammatory myositis (including anti-synthetase syndrome) and rheumatoid arthritis. Non-specific interstitial pneumonia (n = 12) and usual interstitial pneumonia (n = 11) were the predominant radiological patterns. The sustained improvement in PFTs was observed from the start of RTX, with a statistically significant increase in DLCO from basal to one year after RTX (mean + 4.2%, p = 0.024). Overall, there were no differences when comparing PFT outcome according to the radiological pattern or the specific type of AD. In conclusion, RTX constitutes a good therapeutic option to preserve lung function in patients with AD-ILD, regardless of the radiological pattern or the underlying AD.

Interstitial lung disease (ILD) increases morbidity and mortality in patients with rheumatoid arthritis (RA). Although the pathogenesis of ILD associated with RA (RA-ILD⁺) remains poorly defined, vascular tissue is crucial in lung physiology. In this context, endothelial progenitor cells (EPC) are involved in endothelial tissue repair. However, little is known about their implication in RA-ILD⁺. Accordingly, we aimed to investigate the potential role of EPC related to endothelial damage in RA-ILD⁺. EPC quantification in peripheral blood from 80 individuals (20 RA-ILD⁺ patients, 25 RA-ILD⁻ patients, 21 idiopathic pulmonary fibrosis (IPF) patients, and 14 healthy controls) was performed by flow cytometry. EPC were considered as CD34⁺, CD45^low, CD309⁺ and CD133⁺. A significant increase in EPC frequency in RA-ILD⁺ patients, as well as in RA-ILD⁻ and IPF patients, was found when compared with controls (p < 0.001, p = 0.02 and p < 0.001, respectively). RA-ILD⁺ patients exhibited a higher EPC frequency than the RA-ILD⁻ ones (p = 0.003), but lower than IPF patients (p < 0.001). Our results suggest that EPC increase may represent a reparative compensatory mechanism in patients with RA-ILD⁺. The degree of EPC frequency may help to identify the presence of ILD in RA patients and to discriminate RA-ILD⁺ from IPF.

Interstitial lung disease (ILD) constitutes the most critical comorbidity in autoimmune diseases (ADs) and its early diagnosis remains a challenge for clinicians. Accordingly, we evaluated whether E-selectin, ICAM-1, and ET-1, key molecules in endothelial damage, could be useful biomarkers for the detection of AD-ILD⁺. We recruited patients with rheumatoid arthritis (RA)-ILD⁺ (n = 21) and systemic sclerosis (SSc)-ILD⁺ (n = 21). We included comparison groups of patients: RA-ILD⁻ (n = 25), SSc-ILD⁻ (n = 20), and idiopathic pulmonary fibrosis (IPF) (n = 21). Serum levels of these proteins were determined by ELISA. E-selectin, ICAM-1, and ET-1 serum levels were increased in RA-ILD⁺ and IPF patients in comparison to RA-ILD⁻ patients. Additionally, SSc-ILD⁺ and IPF patients exhibited higher ICAM-1 levels than those with SSc-ILD⁻. The ability of E-selectin, ICAM-1, and ET-1 to discriminate RA-ILD⁺ from RA-ILD⁻ patients, and ICAM-1 to distinguish SSc-ILD⁺ from SSc-ILD⁻ patients was confirmed using ROC curve analysis. Furthermore, elevated levels of ET-1 and E-selectin correlated with lung function decline in RA-ILD⁺ and SSc-ILD⁺ patients, respectively. In conclusion, our findings support the relevant role of E-selectin, ICAM-1, and ET-1 in RA-ILD⁺ patients as well as of ICAM-1 in SSc-ILD⁺ patients, constituting potential screening blood biomarkers of ILD in AD. Moreover, this study suggests ET-1 and E-selectin as possible indicators of worsening lung function in RA-ILD⁺ and SSc-ILD⁺ patients, respectively.