Systemic sclerosis (SSc) is an autoimmune connective tissue disease, characterized by immune dysregulation and progressive fibrosis. Interstitial lung disease (ILD) is the most common cause of death among SSc patients and there are currently very limited approved disease-modifying treatment options for systemic sclerosis-related interstitial lung disease (SSc-ILD). The mechanisms underlying pulmonary fibrosis in SSc-ILD are not completely unraveled, and knowledge on fibrotic processes has been acquired mostly from studies in idiopathic pulmonary fibrosis (IPF). The incomplete knowledge of SSc-ILD pathogenesis partly explains the limited options for diseasemodifying therapy for SSc-ILD. Fibrosis in IPF appears to be related to aberrant repair following injury, but whether this also holds for SSc-ILD is less evident. Furthermore, immune dysregulation appears to contribute to pro-fibrotic responses in SSc-ILD, perhaps more than in IPF. In addition, SSc-ILD patient heterogeneity complicates the understanding of the underlying mechanisms of disease development, and more importantly, limits correct clinical diagnosis and treatment effectivity. Therefore, there is an unmet need for patient-relevant (in vitro) models to examine patient-specific disease pathogenesis, predict disease progression, screen appropriate treatment regimens and identify new targets for treatment. Technological advances in in vitro patient-relevant disease modeling, including (human induced pluripotent stem cell (hiPSC)-derived) lung epithelial cells, organoids and organ-on-chip technology offer a platform that has the potential to contribute to unravel the underlying mechanisms of SSc-ILD development. Combining these models with state-of-the-art analysis platforms, including (single cell) RNA sequencing and (imaging) mass cytometry, may help to delineate pathogenic mechanisms and define new treatment targets of SSc-ILD.
BackgroundInterstitial lung disease (ILD) is a spectrum of inflammatory and fibrotic lung diseases, and can be associated with RA (RA-ILD). The reported prevalence ranges from 1.8 to 58 percent, depending on the definition and diagnostics.ObjectivesTo investigate the incidence and prevalence of RA-ILD in different countries worldwide.MethodsPatients of 5 countries from 2 observational databases were studied. Patients from India, Mexico, South Africa (two clinics) and Colombia with a physician-based RA diagnosis were selected from the observational METEOR database. From the Leiden EAC in the Netherlands, patients with early RA (1987 ACR/ 2010 ACR/EULAR criteria) were included. A clinical diagnosis of RA-ILD was based on chest X-ray or CT. X-ray was performed at the first visit in India, South Africa and the Netherlands and on clinical indication in all countries.Prevalence of RA-ILD at the end of follow-up was calculated for each country. Incidence rates (IR) were calculated in patients with newly diagnosed RA and an available baseline visit. Patient characteristics were described, comparing patients with and without RA-ILD using appropriate statistical tests.ResultsWithin the five countries 16,667 patients with RA, both newly diagnosed and with longer RA disease duration, were evaluated. Prevalence and incidence of RA-ILD differed per country. The prevalence of RA-ILD at the end of follow-up was 0.7% (84/11,733) in India (mean follow-up 12±20 months), 2.1% (9/427) in Mexico (mean follow-up 17±27 months), 2.0% (21/1,077) in the Netherlands (mean follow-up 83±71 months), 3.0% (19/629) in South Africa (mean follow-up 20±21 months) and 0.7% (18/2,747) in Colombia (mean follow-up 14±12 months).The IR of RA-ILD in newly diagnosed RA patients in India was 1.6 (95% CI 1.0-2.5) per 1000 person years. In the Netherlands the IR was 3.8 (95% CI 1.6-9.1) per 1000 person years. In South Africa the IR was 6.6 (95% CI 2.5-17.5) per 1000 person years. For Mexico and Colombia, no IR could be calculated.Patient characteristics are described in Table 1. In India and Mexico, patients with RA-ILD were older. In 4 of 5 countries RA-ILD patients were more often male. Higher inflammatory markers and more RF positivity were seen in RA-ILD patients in India and the Netherlands. In South Africa, patients with RA-ILD more often had a history of smoking. ACPA positivity was more frequent in RA-ILD patients from India, but less frequent in RA-ILD patients from South Africa.Table 1.Patient characteristics at the first available visitIndiaMexicoSouth AfricaNetherlandsColombiaRA-ILD (n=84)no RA-ILD (n=11,703)RA-ILD (n=9)no RA-ILD (n=418)RA-ILD (n=19)no RA-ILD (n=610)RA-ILD (n=21)no RA-ILD (n=1,077)RA-ILD (n=18)no RA-ILD (n=2,729)Age (years)57.9±10.646.6±15.362.1±13.352.7±12.652.8±10.250.5±12.857.4±9.255.8±14.561.2 (15.9)59.1 (13.6)p<0.0010.0270.420.600.50Symptom duration (months)47.9(18.0-95.9)59.9(23.9-143.9)108.4(49.3-206.8)68.2(46.7-159.6)25.0(8.3-58.4)45.3(13.1-92.5)4.0(1.9-7.8)4.0(1.6-8.0)89.1(37.9-180.9)111.2(67.6-140.6)p value0.0290.320.180.980.38Sex (female)77%85%67%90%84%82%48%68%78%89%p0.0430.0270.840.0550.12Ever smoker3%1%11%13%93%28%65%62%*p0.270.89<0.0010.81DAS286.3±1.36.0±1.44.5±1.74.6±1.44.9±0.95.2±1.45.2±0.75.1±1.3*p0.110.840.540.80ESR (mm/h)91.5±29.976.7±32.830.7±16.69.0±13.345.0±22.837.1±28.844.3±23.532.0±25.3*p<0.0010.770.260.027Patient global assessment51.2±21.053.8±18.327.8±31.144.6±27.842.6±12.060.1±24.931.5±26.441.1±25.322.2±19.331.0±21.5p0.260.0750.0040.110.084ACPA positive94%81%*83%96%62%54%*p value0.0110.0080.45RF positive95%83%*94%98%86%57%*p0.0030.310.009Data are presented as mean±SD, median (IQR), %.*Insufficient data availableConclusionPrevalence and incidence of RA-ILD varied between the four countries with the highest prevalence and incidence in South Africa. These differences might be partially explained by differences in diagnostic approaches, and potentially in patient populations, used therapies and comorbidity.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsSascha L Heckert Grant/research support from: Bristol-Myers Squibb (BMS), Tjardo Maarseveen: None declared, Emiel R Marges: None declared, Arvind Chopra: None declared, David Vega-Morales: None declared, Riette du Toit: None declared, Lai-Ling Winchow: None declared, Carlos Enrique Toro Gutierrez: None declared, Rachel Knevel: None declared, Annette van der Helm – van Mil: None declared, Thomas Huizinga: None declared, Cornelia Allaart: None declared, Sytske Anne Bergstra: None declared.
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