Objectives To evaluate the Medical Research Council (MRC) dyspnoea scale and serum Microfibrillar-associated protein 4 (MFAP4) levels for the detection of respiratory impairment in newly diagnosed rheumatoid arthritis (RA).Methods Patients underwent blood tests, pulmonary function tests (PFT) and dyspnoea assessment using the MRC scale. Respiratory impairment was defined as a diffusion capacity of the lungs for carbon monoxide (DLCO) <80% predicted or FEV1/FVC <70%. The primary outcomes were the MRC and MFAP4’s sensitivity, specificity, and diagnostic odds ratio (DOR) with 95% confidence intervals (CI).Results One hundred and thirty-one patients had available baseline tests. Mean age was 57.7 years (SD: 10.9), 61% were female, and 45% had respiratory impairment. For MRC score ≥ 2, the sensitivity was 39.0% (95% CI 26.5; 52.6), specificity 76.4% (95% CI 64.9; 85.6), and DOR 2.07 (95% CI 0.97; 4.40). For MFAP4 > 29.0 U/mL, the sensitivity was 62.7% (95% CI 49.1; 75.0), specificity 56.9% (95% CI 44.7; 68.6), and DOR 2.22 (95% CI 1.10; 4.50). The DOR was 3.01 (95% CI 1.27; 7.16) for MFAP4 detecting respiratory impairment when adjusted for age, sex and smoking status.Conclusion The MRC dyspnoea score and unadjusted MFAP4 levels were poor predictors of respiratory impairment in patients with early treatment-naïve rheumatoid arthritis.

Background: Interstitial lung disease (ILD) in Rheumatoid Arthritis (RA) is associated with increased mortality, and methods of detection are warranted [1]. It is generally recommended that RA patients with respiratory symptoms are assessed by HRCT. However, the resources of HRCT may be scarce, and other lung disease, such as Chronic Obstructive Pulmonary Disease, are more prevalent in this population [2,3]. There are currently no other studies on the proportion of patients having ILD in RA with respiratory symptoms, nor do we have an effective way, other than HRCT, to differentiate ILD from other lung disease in RA. Objectives: The objective was to determine the diagnostic accuracy of thoracic ultrasound (TUS) for detecting (ILD) in rheumatoid arthritis (RA) with respiratory symptoms. Methods: Individuals with RA visiting their local Rheumatological outpatient clinics in the Region of Southern Denmark were systematically screened for respiratory symptoms, defined as one of the following: More easily dyspnoeic than others of same age (>2 months duration), daily cough (> 2 months duration), recurrent pneumonia (>1/year), prior severe pneumonia requiring hospitalization or a chest X-ray indication interstitial abnormalities. Patients were not eligible if they had a chest high-resolution CT (HRCT) <12 months or were already diagnosed with ILD. TUS was performed before HRCT. TUS was positive for ILD if there were either ≥10 B-lines or bilateral thickened and fragmented pleura present. The primary outcomes were TUS’s sensitivity, specificity, and positive predictive value (PPV) and negative predictive value (NPV), evaluated by a blinded TUS expert. An ILD-specialized thorax radiologist assessed HRCT as the reference standard. Results: 80 participants with RA and respiratory symptoms were consecutively included. The participants had a mean age of 64.6 (SD: 11.1) years, 55 (69%) female. 77 participants received HRCT <30 days after TUS, and 23 (30%) had ILD on HRCT. TUS had a sensitivity of 82.6% (95% CI: 61.2 to 95.0) and a specificity of 51.9 (95% CI: 37.8 to 65.7), corresponding to a PPV of 42.2% (95%CI 27.7 to 57.8%) and an NPV of 87.5% (95% CI 71.0% to 96.5%). Conclusion: Implementation of systematic screening for respiratory symptoms combined with TUS can reduce diagnostic delay of ILD in RA. REFERENCES: [1] Stainer A, et al.. Front Med (Lausanne) 2023; 10: 1129939.[2] Hyldgaard C, et al. Respir Med 2018; 140: 101-7.[3] Hyldgaard C, et al.. Ann Rheum Dis 2017; 76(10): 1700-6.Figure abbreviations: RA=Rheumatoid Arthritis, ILD=Interstitial Lung Disease, TUS=Thoracic ultrasound, HRCT= High Resolution CT Acknowledgements: We thank the participants and study collaborators in the Rheumatological departments in the Region of Southern Denmark as well as collaborators in the Department of Respiratory Medicine, Odense University Hospital. Thanks to our three Danish patient research partners from the Rheumatology Research Unit (LB, OA, and LP) for their valuable and critical feedback. This work was supported by the Region of Southern Denmark’s Ph.D.-grant [19/37084], Odense University Hospital [A4113 and A5095], and Ph.D.-grant from the University of Southern Denmark. A core grant from the Oak Foundation [OCAY-18-774-OFIL] supports the Section for Biostatistics and Evidence-Based Research, the Parker Institute, Bispebjerg and Frederiksberg Hospital. Disclosure of Interests: Bjørk K. Sofíudóttir: None declared, Stefan Harders: None declared, Christian B. Laursen: None declared, Philip Rask Lage-Hansen: None declared, Sabrina Mai Nielsen: None declared, Søren Andreas Just: None declared, Robin Christensen: None declared, Jesper Rømhild Davidsen Grant from Boehringer Ingelheim. Not for this project., Torkell Ellingsen: None declared Table 1CharacteristicsTUS positive(n=47)TUS negative(n=33)STD-diff*Age, years69 (9)59 (11)0·976*Female, n(%)26 (55%)29 (88%)-0·516*BMI, kg/m225·0 (4·5)33·7 (7·4)-1·369**ACPA positive, n(%)32 (68%)16 (48%)0·529*IgM RF positive, n(%)33 (70%)19 (58%)0·389Smoking habitsPack-years19·2 (17·4)11·3 (14.9)0·488Never smoked, n(%)16 (34%)14 (42%)-0·200Duration of respiratory symptoms (Months), Median (IQR)25·0 (6·0 to 72·0)24·0 (6·0 to 41·0)-0·040#HAQ (0-3)0·5 (0·7)0·6 (0·6)-0·184CRP mg/L, Median (IQR)5·2 (2·1 to 13·0)3·9 (1·8 to 13·0)-0·013DAS28CRP2·7 (1·1)3·0 (1·1)-0·291FEV1 % pred.84·2 (25·0)97·2 (20·1)-0·573*FVC % pred.95·2 (19·3)103·0 (17·1)-0·426FEV1/FVC %69·6 (16·4)79·3 (12·9)-0·660*TLC % pred.87·4 (14·0)92·9 (20·7)-0·313DLCO % pred.64·6 (18·1)83·4 (20·7)-0·977**Table 1. Values are Mean (SD), unless otherwise stated. abbreviations: TUS=Thoracic ultrasound, STD-diff=Standardized difference, STD*=Moderate effect size, STD**=large effect size, SD=standard deviation, IQR=Interquartile range, BMI=Body mass index, ACPA=Anti-citrullinated protein antibody, IgM RF=IgM Rheumatoid factor, HAQ=Health assessment Questionnaire, CRP=C-Reactive protein, DAS28CRP=Disease Activity Score-28 for Rheumatoid Arthritis with CRP, FEV1=Forced expiratory volume in 1 second, FVC=Forced vital capacity, TLC=Total lung capacity, DLCO=Diffusing capacity for carbon monoxide, 6MWD=6-min walk distance, #= Data not complete.

ObjectivesEarly identification of interstitial lung disease (ILD) among patients with rheumatoid arthritis (RA) is a challenge for clinicians. The aim of this study was to evaluate screening algorithms for ILD by comparing the proportion of patients assigned a high-risk profile by three recently proposed models.MethodWe used the four-factor risk score, categorizing patients into high and low risk; the ILD screening criteria, categorizing patients into high, intermediate, and low risk; and the risk score for detection of subclinical RA-ILD, with four different risk categories, on patients with RA followed for 5 years after the RA diagnosis with pulmonary function tests, dyspnoea score, and pulmonary imaging.ResultsThe four-factor risk score identified 22% of the cohort (25/115) as eligible for further ILD investigations, while the ILD screening criteria identified 37% as high risk (43/115) and 34% as intermediate risk (39/115). The risk score for detection of subclinical RA-ILD identified 44% of the cohort as being at increased risk, with 7% in the highest risk group. The agreement between high-risk groups in the two clinical ILD screening models was moderate (kappa 0.43). Three patients in the cohort had clinical or subclinical ILD, and they were identified as high risk in the two clinical models.ConclusionThe three algorithms identified approximately one-third of the cohort as being at increased risk of ILD. Further development and validation of these algorithms are needed to reduce false positives and balance the potential benefit of earlier ILD diagnosis and healthcare resources used for respiratory assessment.

OBJECTIVE:To determine the diagnostic accuracy of thoracic ultrasound (TUS) for detecting interstitial lung disease (ILD) in rheumatoid arthritis (RA) with respiratory symptoms. METHODS:Individuals with RA visiting rheumatologic outpatient clinics in the Region of Southern Denmark were systematically screened for dyspnea, cough, recurrent pneumonia, prior severe pneumonia, or a chest x-ray indicating interstitial abnormalities. Eighty participants with a positive screening were consecutively included. Individuals were not eligible if they had a chest high-resolution computed tomography (HRCT) less than 12 months ago or were already diagnosed with ILD. A blinded TUS expert evaluated TUS, and TUS was registered as positive for ILD if at least 10 B-lines or bilateral thickened and fragmented pleura were present. The primary outcomes were TUS's sensitivity, specificity, and positive predictive value and negative predictive value. An ILD-specialized thoracic radiologist assessed HRCT, followed by a multidisciplinary team discussion, which was the reference standard. The accepted window of HRCT was less than 30 days after TUS was performed. RESULTS:A total of 77 participants received HRCT less than 30 days after TUS, and 23 (30%) were diagnosed with ILD. TUS had a sensitivity of 82.6% (95% confidence interval [CI] 61.2%-95.0%) and a specificity of 51.9% (95% CI 37.8%-65.7%), corresponding to a positive predictive value of 42.2% (95% CI 27.7%-57.8%) and a negative predictive value of 87.5% (95% CI 71.0%-96.5%). CONCLUSION:To our knowledge, this prospective study is the first to use respiratory symptoms in RA as inclusion criteria. Systematic screening for respiratory symptoms combined with TUS can reduce the diagnostic delay of ILD in RA.

BACKGROUND:Currently, there are no reliable biomarkers for predicting treatment response in chronic inflammatory diseases (CIDs). OBJECTIVE:To determine whether serum microfibrillar-associated protein 4 (MFAP4) levels can predict the treatment response to biological therapy in patients with CIDs. METHODS:The BELIEVE study was originally designed as a prospective, multi-center cohort study of 233 patients with either rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, Crohn's disease, or ulcerative colitis, initiating treatment with a biologic agent (or switching to another). Clinical assessment and blood sample collection were performed at baseline and 14-16 weeks after treatment initiation. The primary analyses included participants with available blood samples at baseline; missing data were handled as non-responders. The patients were stratified into the upper tertile of serum MFAP4 (High MFAP4) versus a combined category of middle and lower tertiles (Other MFAP4). The primary outcome was the proportion of patients with clinical response to biologic therapy after 14-16 weeks. RESULTS:211 patients were included in the primary analysis population. The mean age was 43.7 (SD: 14.8) years, and 120 (59%) were female. Positive treatment response was observed in 41 (59%) and 69 (49%) for High MFAP4 and Other MFAP4, respectively. When adjusting for pre-specified variables (CID, age, sex, smoking status, and BMI), the adjusted OR was 2.28 (95% CI: 1.07 to 4.85) for a positive treatment outcome in the High MFAP4 group. CONCLUSION:A high MFAP4 status before initiating biological treatment is associated with a positive clinical response, when adjusting for confounding factors.

Objective: Pulmonary disease is a major cause of excess mortality among patients with rheumatoid arthritis (RA). Interstitial lung disease (ILD) is a feared complication, but the benefit of screening is unknown. The aim of this study was to assess the frequency of pulmonary disease, including ILD, in early RA. Method: Patients with newly diagnosed RA were recruited prospectively at a single centre and underwent systematic pulmonary function tests (PFTs) and computed tomography (CT) scans at inclusion and after two years. Results: The study included 150 patients (mean age 57 years, 63% female; 59% current or former smokers). Of these, 136 underwent baseline PFTs and 137 CT. Mean forced expiratory volume in one second was 99% predicted and forced vital capacity 106%. Mean diffusing capacity of the lungs for carbon monoxide (DLCO) was 84% predicted. Frequently detected CT abnormalities were pulmonary nodules (42%), bronchiectasis (29%), and emphysema (20%). Two patients had clinically significant ILD and six had mild reticulation suggestive of preclinical ILD. No ILD progression was identified at two-year follow-up. Smoking was associated with DLCO<80% (p=0.004), combined hyperinflation and diffusion impairment (residual volume>120% and DLCO<80%) (p=0.004), and visual emphysema on CT (p<0.001). Conclusion: Emphysema and bronchiectasis were common, but most patients had mild disease with preserved lung function. Preclinical or clinical ILD was seen in a minority in this early phase of RA. These findings suggest symptom-based screening and primary intervention focusing on smoking cessation rather than screening for ILD at the time of RA diagnosis.

INTRODUCTION:Pulmonary diseases are significant contributors to morbidity and mortality in patients with rheumatoid arthritis (RA). RA-associated interstitial lung disease (RA-ILD) may be prevalent in up to 30% and clinically evident in 10% of patients with RA. Feasible methods to detect concomitant ILD in RA are warranted. Our objective is to determine the diagnostic accuracy of thoracic ultrasound (TUS) for ILD in patients with RA with respiratory symptoms, by using chest high-resolution CT (HRCT) as the reference standard. Further, we aim to evaluate the diagnostic accuracy for the promising blood biomarkers surfactant protein-D and microfibrillar-associated protein 4 in the detection of ILD in this group of patients.METHODS AND ANALYSIS:By use of a standardised 14 zone protocol patients suspected of having RA-ILD will undergo TUS as index test performed by a junior resident in rheumatology (BKS), who is certified by the European Respiratory Society in performing TUS assessments. Participants form a consecutive series of up to 80 individuals in total. The anonymised TUS images will be stored and scored by the junior resident as well as two senior rheumatologists, who have received training in TUS, and a TUS-experienced pulmonologist. HRCT will be used as the gold standard for ILD diagnosis (reference standard). The two basic measures for quantifying the diagnostic test accuracy of the TUS test are the sensitivity and specificity in comparison to the HRCT.ETHICS AND DISSEMINATION:Data will be collected and stored in the Research Electronic Data Capture database. The study is approved by the Committees on Health Research Ethics and the Danish Data Protection Agency. The project is registered at clinicaltrials.gov (NCT05396469, pre-results) and data will be published in peer-reviewed journals.