A Novel screening protocol for early detection of lung involvement in seropositive and ACPA positive rheumatoid arthritis

doi:10.21203/rs.3.rs-4672518/v1

Download PDF

Research Article

A Novel screening protocol for early detection of lung involvement in seropositive and ACPA positive rheumatoid arthritis

https://doi.org/10.21203/rs.3.rs-4672518/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Background: Seropositive rheumatoid arthritis (RA) is associated with significant cardiovascular and pulmonary morbidity. However, screening for early detection of pulmonary involvement especially interstitial lung disease (ILD) is not established in RA.

Methods: We used a non-invasive radiation-free approach to screen for pulmonary, pleural, or vascular disease manifestation using a pulmonary function test (PFT), a cardiopulmonary exercise test (CPET), echocardiography (ECG), and pleuro-pulmonary transthoracic ultrasound (LUS). We included patients with confirmed diagnosis of seropositive RA according to ACR criteria, but without symptoms for or known cardiopulmonary disease.

Results: We included 67 consecutive patients (78% female, mean age 61±12 years, 48% active or previous smokers), who fulfilled the inclusion criteria and gave written informed consent.

We found 48% of patients with suspected changes in PFT with a diffusion capacity (DLCOc-SB) ≤ 80% among them 7% with forced vital capacity (FVC) ≤ 80%.

In 40% of patients, we found noticeable changes in LUS, 24% with an ILD compatible pattern. ILD was suspected when LUS abnormalities and additional PFT changes were present, which was found in 16% of cases. Other findings included obstructive lung disease (n=11), subpleural consolidation (n=6) including one confirmed lung cancer, minimal pleural effusion (n=6), severe aortic stenosis in bicuspid aortic valve (n=1), and ischemic cardiac disease (n=2). None of the patients showed signs of pulmonary vascular involvement on ECG or CPET.

Conclusions: Screening of asymptomatic RA patients for pulmonary involvement detects a variety of cardiopulmonary comorbidities. ILD was suspected in 16% of cases.

Trial registration: German Register of Clinical Studies (DRKS00028871).

interstitial lung disease

seropositive rheumatoid arthritis

non-invasive

pulmonary function test

lung ultrasound

PFT

LUS

ILD

According to the World Health Organization (WHO), rheumatoid arthritis (RA) is the most common inflammatory rheumatic disorder with a prevalence of 0.8–5.5% and an annual incidence between 25–60 per 100,000 adults per year. About 65–80% of RA patients have a positive (IgM) rheumatoid factor (seropositive RA). Detection of anti-citrullinated peptide antibodies (ACPA) are highly specific for RA (sensitivity approximately 70%, specificity 95%) and indicate a more severe and destructive disease course with higher serological inflammatory activity [1].

Besides cardiovascular comorbidities, pulmonary manifestation in RA is well known and present with different forms, such as obstructive lung disease, bronchiectasis, pleural manifestation, pulmonary nodules, or treatment related pulmonary complications. The occurrence of pulmonary hypertension (PH) is considered as low in RA [2]. Interstitial lung disease is the most frequent pulmonary manifestation of RA (RA-ILD) and may present as usual interstitial pneumonia (UIP), non-specific interstitial pneumonia (NSIP), organizing pneumonia, or diffuse alveolar damage [3]. Thus, the ILD disease course is highly variable. RA-ILD may develop at any stage of RA and may precipitate even before joint manifestation. It is associated with increased morbidity and mortality and serves as a determinant for poorer RA prognosis [3, 4]. So far, several risk factors for the development of RA-ILD have been suggested such as presence of specific RA antibodies, longer disease duration, high disease activity, active smoking, and male gender [2, 3].

About 3–6% of RA patients develop clinically significant RA-ILD, but many patients are diagnosed late at an advanced stage of the disease [5, 6]. Early diagnosis of RA as well as possible associated lung disease is warranted especially in the advent of effective treatment strategies [7].

Screening for ILD in RA has been previously reported. The rate of detected subclinical ILD ranges from 20–60% using high-resolution thoracic computed tomography scans (HRCT), but the course of these findings is highly variable [8].

Several methods have been reported for the assessment of ILD. In clinical practice, auscultation and PFT are mainly used. However, PFT is dependent on patients´ cooperation and methodological issues and detects ILD mainly at an advanced disease stage. HRCT has recently been proposed in several screening studies for RA-ILD [3, 8, 9]. While HRCT is regarded as the most sensitive measure for the detection of ILD and for differential ILD subtype diagnosis, it is associated with considerable radiation exposure, organizational issues, and medical expenses [3].

Lung ultrasound (LUS) has been suggested as an easy-to-use non-radiation-based imaging method. It can detect subpleural interstitial changes using several ultrasound criteria [9, 10, 11]. Some studies have evaluated the use of LUS in several forms of ILD diseases with a reported sensitivity between 73–100% and a specificity of 66–97% compared to HRCT [12].

In this prospective study, we used PFT and LUS as a screening tool in consecutive RA patients without cardiopulmonary disease to detect lung and especially interstitial lung changes.

In this prospective study, we included patients with seropositive and ACPA positive RA for screening of pulmonary involvement and cardiac comorbidity.

Inclusion criteria were:

Patients with diagnosis of seropositive and ACPA-positive RA according to Aletaha-EULAR/ACR classification criteria [13] regardless of time of diagnosis and current or previous disease-modifying anti-rheumatic drugs (DMARDs) such as conventional synthetic csDMARDs (e.g. methotrexate, leflunomide), targeted synthetic tsDMARDs (e.g. small molecules tofacitinib, baricitinib, upadacitinib), and biological bDMARDs (e.g. TNF alpha blockers, rituximab, tocilizumab)
No known or previously diagnosed cardiopulmonary disease
No symptoms of cardiopulmonary impairment, especially no cough, sputum production, breathlessness on exertion / at rest, or thoracic discomfort / chest pain
No lung function screening in the last six months before inclusion in the study.
Written informed consent sheet consistent with the International Conference on Harmonization Harmonized Tripartite Guideline for Good Clinical Practice (ICH-GCP) and local legal requirements must be signed prior to the start of the study
Male or female patients ≥ 18 years at baseline
No signs of active infection, especially negative test for SARS-CoV 2 infection (PCR or antigen test)

Exclusion criteria were:

Diagnosis of seronegative and/or ACPA negative RA or other forms of arthritis
Known interstitial, obstructive, restrictive, pleural, or other chronic lung disease
Known cardiovascular disease, e.g. valvular heart disease, coronary artery disease, manifest systolic or diastolic heart failure, pulmonary vascular disease
A positive SARS-CoV 2 test (PCR) or other active infection
Exclusion of patients with other underlying diseases.
Creatinine clearance < 30 mL/min calculated using the Cockcroft-Gault formula at study entry
Patients with chronic underlying liver disease (Child Pugh A, B or C hepatic impairment)
Other investigative therapies administered within 1 month or 6 half-lives (whichever is longer) prior to study inclusion
Other clinically significant pulmonary pathologies in the opinion of the investigator
Other medical conditions that could interfere with the testing methods or, in the opinion of the investigator, could interfere with study participation or put the patient at risk from participation in this study
Major operations planned
Pregnancy
Patients unable to understand or follow study processes, including being unable to complete questionnaires unaided
Active alcohol or drug abuse established in the investigator’s opinion

After informed consent patients underwent a screening protocol including:

History and physical examination including smoking status and medication, especially DMARDs time since diagnosis,
Rheumatological condition of the patient according to disease specific evaluation and questionnaires (FFbH, PHQ- 2, EQ-5D, FACIT, NRS Health, PHQ-4, RADAI, RAID, WHO-5, WPAI-GH), disease activity (scores such as VAS doctor, VAS patient, TJC, SJC, CDAI, SDAI, DAS28),
Inflammatory activity based on CRP, BKS, RF, ACPA antibodies
PFTs including spirometry, body plethysmography, and diffusion capacity with helium-CO method and correction for hemoglobin using global lung initiative GLI normal values.
ECG at rest
Routine TTE according to routine protocol
CPET on a treadmill in erect body position including 12 lead ECG, analysis of expiratory gas samples using a CPET mask, blood gas analysis at rest and during exercise from the arterialized earlobe, oxygen saturation and non-invasive blood pressure measurement. For exercise, we used a ramp protocol with a 1-minute preload phase and a maximum workload considering the patient’s physical condition to be reached after 10 minutes. The anaerobic threshold (AT) was determined using the V slope method.

For transthoracic pleuropulmonary ultrasound (LUS) we used a convex 2.5 MHz probe (Hitachi Aloka ProSound Alpha 6 or Hitachi Arietta V70). The patient sat in an erect position. Using a prespecified protocol according to [17], the investigation was performed examining dorsal, lateral, and ventral views including the whole thorax. LUS was performed in agreement by 2 investigators (F.R, M.H., W.v.W.) with the presence of pleural effusion, diaphragm function, and subpleural consolidations.

For ILD evaluation, we used established sonographic markers for ILD signs based on changes in the pleural line, such as fragmentation and thickening [10] and the presence of hyperechoic vertical artefacts (B lines) > 5 per field of view [11].

RA-ILD was suspected if impaired PFT with DLCOc-SB / KCOc-SB < 80% pred or FVC < 80% and signs of interstitial changes on LUS in the absence of other abnormal cardiopulmonary findings at time of screening were detected.

Patients with conspicuous findings on LUS, e.g. signs of ILD or consolidations, were recommended to undergo further evaluation including HRCT.

Statistics

To characterize the collected sample, in a first step a descriptive analysis of the sample properties was carried out. The trend in the form of mean and median, as well as the distribution (standard deviation SD, interquartile range IQR) and the frequency (absolute and relative frequency) were analyzed.

For the primary endpoint (according to the estimated number of cases), a two-tailed binomial test of the sample was used to determine whether lung involvement occurs more frequently than previously reported in the literature. The calculation of the estimated case number was based on our hypothesis that patients with seropositive and ACPA positive RA have a higher prevalence (expected 10% or more) of lung involvement (ILD of known etiology) than assumed (depending on the literature and methods 3–6% [5, 6]; effect size g = 0.04; error level (alpha 5%, beta 20%, separation strength 80%)).

Further analyses were then performed for the secondary endpoints and the corresponding hypotheses. Considered were e.g. logistic regression models to identify risk factors for lung involvement, subgroup comparisons in the context of t-tests for independent samples or Wilcoxon rank-sum tests, or frequency distribution comparisons with the chi-square test.

Data management and ethics

Patients’ data were pseudonymized, collected, and stored in a password protected file on a non-internet-enabled computer.

The study was reported with a positive ethics vote to the German Register of Clinical Studies (DRKS00028871) and approved by the ethics committee of the University of Munich, Germany, project number 21-1138.

Participants

Between April 2022 and December 2024, we included 67 consecutive RA patients, who fulfilled the inclusion criteria and gave written informed consent. None of the patients complained of respiratory symptoms, especially no dyspnea at rest or exercise, cough, or chest pain. The mean age was 61 ± 12 years, 78% of patients were female. A total of 40% were active or previous smokers with a smoking history of 20 ± 20 mean pack years.

The mean duration of RA disease since diagnosis was 9.3 ± 8.5 years. With regard to RA disease activity, patients showed a mean DAS 28-CRP of 2.3 ± 0.9 (equivalent to remission of RA), a mean CDAI 6.2 ± 6.6 (indicating low RA disease activity), a mean SDAI 6.7 ± 6.6 (indicating low disease activity). Forty-one patients were treated with csDMARDs, 13 patients with tsDMARDs, and 33 patients with bDMARDs, while 7 patients were treated with steroids at the time of the examination (see Table 1).

Table 1

Comparison of nonILD and susILD groups with respect to clinical, rheumatological, and functional parameters^#
Characteristics	Total patients (n = 67)	No ILD signs (n = 56)	Suspected ILD (n = 11)
Female	52 (78%)	43 (77%)	9 (82%)
Age	60.8 ± 11.7	60.0 ± 11.3	64.8 ± 13.1
BMI	25.4 ± 4.5	25.1 ± 4.5	26.5 ± 4.8
Active or previous smoking	N = 27 (40%)	N = 19 (33%)	N = 8 (73%)*
Pack years	20 ± 20	17 ± 19	33 ± 21
DAS 28-CRP	2.3 ± 0.9	2.3 ± 0.9	2.2 ± 0.8
CCP titer	219 ± 100	221 ± 101	223 ± 100
csDMARDs	N = 41 (61%)	N = 33 (59%)	N = 8 (73%)
tsDMARDs	N = 13 (19%)	N = 12 (21%)	N = 1 (9%)
bDMARDs	N = 33 (49%)	N = 27 (48%)	N = 6 (55%)
DLCOc-SB (%pred)	78 ± 19	80 ± 17	66 ± 15*
KCOc-SB (%pred)	88 ± 18	91 ± 17	72 ± 10*
FVC (%pred)	105 ± 17	106 ± 17	99 ± 17
CPET Watt max	131 ± 41	135 ± 41	114 ± 37
VO2max ml/kg/min	22.6 ± 8.2	23.6 ± 8.4	18.3 ± 5.8*
VO2- AT ml/kg/min	16.8 ± 6.8	17.5 ± 7.0	13.5 ± 5.3*
EQCO2 slope	27.3 ± 5.7	26.7 ± 5.6	29.9 ± 5.2
^#Given are mean ± SD; *p < 0.05

Fourteen patients (20%) experienced a COVID 19 infection within the last 2 years prior to study inclusion. The previous COVID 19 infection had no impact on the results of the study.

PFT

All participants underwent PFT. In the total cohort, the mean FEV1 was 2.6 ± 0.6 l [97(18) %pred], mean FVC 3.5 ± 0.7 l [105(17) %pred], mean TLC 5.9 ± 1.2 l [107(16) %pred], mean DLCOCc-SB was 77 (18) %pred, and mean KCOc-SB 88 (17) %pred.

Eleven patients showed an obstructive airway pattern (FEV1/FVC < 70%), 2 patients a combined obstructive – restrictive pattern, and 1 patient a restrictive pattern (TLC < 80% pred). An impaired diffusion capacity was measured in 32 patients with DLCOc-SB < 80% and in 23 patients with KCOc < 80%.

LUS

Afterwards, LUS was performed in all patients. It showed a normal pleuropulmonary imaging in 40 patients (60%). Six patients (9%) presented with minimal pleural effusions (not amenable for pleurocentesis), in 6 patients (9%) subpleural consolidations were detected. Further findings included unilateral B lines in previous pleural trauma (n = 2) and unilateral diaphragm dysfunction (n = 2 patients).

One patient showed bilateral fragmentation, pleural thickening, and B lines as well as pleural effusion, impaired renal function, and impaired cardiac function on TTE. Therefore, changes were related to fluid overload in cardiorenal compromise and not suspicious for ILD.

In 16 patients (24%), LUS revealed bilateral pleural fragmentation (n = 12), pleural thickening (n = 6), and B lines (n = 9) as signs of possible ILD.

TTE

Then a TTE was performed in all participants. It showed that the mean systolic LV function was 64 ± 7%, the mean sPAP corrected for CVP was 26 ± 6 mm Hg, and the mean RV-TAPSE was 23 ± 4 mm. One patient presented with severe aortic stenosis due to bicuspid aortic valve requiring further intervention. Other findings included mild diastolic left ventricular dysfunction (n = 16), left ventricular hypertrophy (n = 6), septal and anterior hypokinesia (n = 2), minimal mitral valve prolapse (n = 1), and minimal aortic insufficiency (n = 53; see Table 2). None of the patients showed signs of pulmonary vascular involvement.

Table 2

Cardiopulmonary comorbidities in 67 RA patients
Disease	Current study	Comments
Obstructive lung disease	N = 11
Bronchi(olo)ectasis	N = 3	Underestimated as not able to detect by LUS
Pleural effusion	N = 6	1x bilateral due to fluid overload
Consolidations	N = 6	1x NSCLC
ILD	N = 11	Suspected on PFT and LUS, confirmed in 3 pts.
Unexplained diffusion impairment	N = 12
Systemic hypertension	N = 12
LV hypertrophy	N = 6
Diastolic LV dysfunction	N = 16	Mild, detected on TTE
Ischemic heart disease	N = 2	Suspected on TTE
Valvular heart disease	1x severe AoSt, 5x mild AI, 1x MVP
Pericardial effusion	N = 1	Found on HRCT
PH	none

CPET

In a last step, patients underwent cardiopulmonary exercise tests. Two patients did not undergo exercise due to severe aortic stenosis and withdrew consent for CPET. Sixty-five patients were able to perform CPET with a peak VO2 of 22.6 ± 8.2 ml/kg/min (95 ± 27%pred) and a maximum workload of 131 ± 41 Watt (111 ± 27%pred). The AT was detected at 16.8 ± 6.8 ml/kg/min (70 ± 26%pred VO2 peak). Slope of breathing equivalent for CO2 was 27.3 ± 5.7. None of the patients developed hypoxemia or signs of cardiac ischemia during or after exercise.

Assessment of ILD-suspicion

We assessed which patients could possibly have ILD. In 16 patients an ILD compatible pattern was detected on LUS (24%). Among them, 11 patients showed impaired PFT with DLCOc-SB/KCOc-SB ≤ 80% pred (n = 10) and FVC < 80% (n = 2). This group was suspected of having ILD (susILD), which was 16% of patients.

Comparison between non-ILD group (nonILD) and ILD suspected group (susILD)

Comparing the patients in the susILD (n = 11) and nonILD group (n = 56) (see Table 1), patients in the susILD group included significantly more active or previous smokers with a tendency towards higher pack years. They had a lower diffusion capacity and a reduced exercise capacity measured by VO2 peak at maximum exercise and VO2 at AT during CPET. Both groups showed comparable gender and age distribution, lung volumes, as well as rheumatic disease activity indices. Patients with susILD were more often on treatment with csDMARDs in combination with bDMARDs, while the nonILD group was more often on monotherapy with tsDMARDs. Data are shown in Table 1.

HRCT

In the follow up, 11 patients underwent HRCT outside the study for further evaluation of LUS findings.

In the susILD group, 4 patients underwent HRCT. Three patients demonstrated signs compatible with ILD: 2 with subpleural reticular changes and 1 patient with basal lung scaring. One patient with significant reduced diffusion capacity presented with bilateral upper lobe emphysema.

In the nonILD group, 7 patients underwent HRCT. Two patients showed ILD with reticular changes but also bronchi(olo)ectasis. Both exhibited normal PFT including diffusion capacity although both had possible ILD signs on LUS. One patient with normal PFT but possible ILD signs on LUS had minimal pericardial effusion on HRCT.

In one patient with significantly impaired diffusion capacity but normal LUS, HRCT revealed bronchi(olo)ectasis.

Three patients underwent HRCT due to consolidations on LUS. This was confirmed as minimal nodular changes (n = 1), postinfectious changes (n = 1), and a tumor- suspected lesion, which was diagnosed as non-small lung cancer during bronchoscopy. The patient underwent curative lung resection in stage I disease.

Lung involvement in RA can occur in a variety of clinically meaningful manifestations. The development of ILD in RA is rare but of therapeutic relevance with a potential prognostic impact [3].

In this study, we used a screening approach for lung manifestation in 67 consecutive seropositive and ACPA positive RA patients based on LUS imaging and PFT. Using these combined techniques, we found suspected lung involvement in 34 patients (51%), among them 11 patients with obstructive lung disease (16%), 6 patients with pleural effusion (9%), and 6 patients with subpleural consolidations (9%). In 11 patient we found a PFT-LUS pattern suggestive for ILD (16% susILD). As 4 of these patients underwent HRCT, ILD was confirmed in 3 patients. In the 4th patient (non-smoking), HRCT revealed upper lobe emphysema as the cause of impaired diffusion capacity.

We used a screening protocol to combine changes in PFT, especially in diffusion capacity and LUS, using an imaging and functional method to overcome the risk of overdiagnosis. Among PFT, diffusion capacity is traditionally used to detect early lung involvement in rheumatic disease. However, it is dependent on patient compliance and differences in technical equipment. Therefore, we used DLCOc-SB as well as KCOc-SB to assess impaired diffusion capacity. In our cohort, we found 12 patients (18%) with impaired diffusion capacity, but no signs of ILD or pulmonary vascular disease. In addition to PFT, we used LUS as a feasible imaging method. HRCT is the gold standard for imaging screening for ILD and is well established in high prevalence diseases such as systemic sclerosis [14]. However, this is currently challenged by LUS as a radiation free and easy to use method [12]. This is particularly important in diseases with a high population prevalence but a relatively low ILD prevalence as in RA. LUS findings have a broad differential diagnosis and should be interpreted according to the clinical situation [15]. Indeed, one patient with ILD compatible signs on LUS presented with bilateral pleural effusions and an impaired cardiac function on TTE consistent with cardiac failure and pulmonary congestion.

Imaging changes might precede PFT changes. For example, 2 patients in our cohort had normal PFT but ILD changes on LUS. This was confirmed by HRCT. Nevertheless, the presence of susILD was associated with lower exercise performance with significantly lower VO2 at peak exercise and AT compared to nonILD. This underlines the clinical impact of the finding.

In our small cohort, there was no gender difference between the susILD and the nonILD group. However, there were significantly more previous and active smokers in the susILD group. Smoking is an established risk factor for ILD in RA [3].

We found no significant difference between both groups with respect to clinical and serological activity of RA as displayed by DAS-28, CDAI, SDAI, inflammation markers, and CCP level. In our study, there is a trend that monotherapy with tsDMARDs is associated with a lower disease activity and less pulmonary changes. Whether tsDMARD therapy has a positive impact on lung involvement in RA cannot be assessed in this study due to the small number of cases. Recent reports, however, indicate that tsDMARD therapy in patients with RA-ILD appears to have a stabilizing effect on RA-associated lung disease [16]. However, the data are still too sparse to draw conclusions.

Our study supports the growing evidence and experience in using LUS for screening for RA ILD. A combination of functional and imaging methods is required to overcome the limitation of PFT and LUS in ILD- screening. We consider LUS an appropriate and ready to use screening tool for ILD in RA in clinical practice.

In the present study, we found several other cardiopulmonary comorbidities. Obstructive lung diseases, either asthma or COPD, have a reported prevalence of 1–21% in RA [17]. Our study confirmed a high percentage (16%) of obstructive airway patterns. This was probably due to the high rate of ex- and active smokers compared to previous reports [2, 17].

Occurrence of bronchiectasis is well known in RA with a reported prevalence of 3–62% [2, 17]. In our cohort, we found 3 patients with bronchi(olo)ectasis on HRCT. However, this might be an underestimate as LUS is not able to detect bronchi(olo)ectasis and not all patients underwent HRCT.

Among the 6 patients with subpleural pulmonary consolidations, 3 underwent HRCT where lung nodules were confirmed. Lung nodules are well known in RA (up to 30% of patients) and might be related to therapy as well as additional exposure [2]. One non-smoking patient in our cohort was diagnosed with NSCLC amenable for curative surgery. There are conflicting data about the risk for lung cancer especially in seropositive RA. According to current guidelines, RA patients with a significant smoking history or other risk factors for lung cancer should be consistently screened for lung malignancy [18]. Lung cancer screening is based on HRCT and beyond the scope of LUS.

We found minimal pleural effusion in 6 patients, among them one patient with bilateral effusion and impaired cardiac function on TTE. Small pleural effusion is a frequent finding in RA up to 70% in postmortem studies [2].

We found several cardiac comorbidities in our cohort among them valvular disease (n = 7), signs of ischemic heart disease (n = 2), and pericardial effusion (n = 1) (see Table 2). The low rate in our screening study might be due to the inclusion of asymptomatic patients. None of the patients showed signs of PH which is compatible with the reported low risk of PH in RA [3, 19].

Our study has several limitations. First, we performed a screening study with a non- radiation approach using PFT and LUS. HRCT as the gold standard in imaging of ILD was not routinely performed. HRCT was also not always performed in individual patients with suspected screening results despite being recommended. Both LUS and PFT are routinely performed to assess ILD. LUS has a high sensitivity and specificity for the detection of ILD [12]. Although it cannot distinguish between distinct ILD patterns, all these patterns have the potential to turn into progressive disease in RA [20]. This underlines the need for a regular screening.

Second, 14 patients (21%) experienced a diagnosed COVID 19 infection within the last 2 years before inclusion in the study. Although we did not find any impact on our study results, an influence on pulmonary function and imaging as well as exercise performance cannot be excluded.

Finally, data on the long-term consequences of these findings are not yet available and need to be reported in the future.

Screening of asymptomatic seropositive and ACPA positive RA patients for pulmonary involvement detects a variety of cardiopulmonary comorbidities. Using LUS and PFT, ILD was suspected in 16% of cases.

ACPA anti-citrullinated peptide antibodies

AI aortic insufficiency

AoSt aortic stenosis

AT anaerobic threshold

BMI body mass index

CCP computed cardiopulmonography

CPET cardiopulmonary exercise test

CRP C-reactive protein

CVP central venous pressure

DLCOc-SB diffusion capacity

DMARDs disease-modifying anti-rheumatic drugs

EQCO2 ventilatory equivalent of carbon dioxide

FVC forced vital capacity

HRCT high-resolution thoracic computed tomography

ILD interstitial lung disease

KCOc-SB CO transfer coefficient

kg kilogram

LUS lung ultrasound

LV left ventricular

max maximum

min minute

ml milliliter

MVP mitral valve prolapse

nonILD no ILD

NSCLC non-small cell lung carcinoma

PFT pulmonary function tests

PH pulmonary hypertension

pred predicted

RA rheumatoid arthritis

SD standard deviation

susILD suspected ILD

TTE transthoracic echocardiography

VO2 maximum oxygen consumption

Ethics approval and consent to participate

The study was approved by the ethics committee of the University of Munich, Germany, project number 21-1138. Participants signed an informed consent form before the start of the screening process.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

Frank Reichenberger: research support, advisory boards and speakers fee from Boehringer Ingelheim and GlaxoSmithKline Ltd.

Florian Popp: nothing to declare in relation to the manuscript

Martin Hoffmann: nothing to declare in relation to the manuscript

Carina Fischinger: nothing to declare in relation to the manuscript

Werner von Wulffen: research support and speakers fee from Boehringer Ingelheim

Nikolaus Kneidinger: nothing to declare in relation to the manuscript

Martin Welcker: research support from Boehringer Ingelheim, Novartis, Abbvie, speakers fee from Boehringer Ingelheim, Novartis, Abbvie, Norsan, Lilly, Galapagos, fees for advisory boards from Boehringer Ingelheim, Novartis, Abbvie, Galapagos, Lilly

Funding

This is an independent, investigator-initiated study supported by Boehringer Ingelheim, Germany. Boehringer Ingelheim had no role in the design, analysis, or interpretation of the results in this study; Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as it relates to Boehringer Ingelheim substances, as well as intellectual property considerations.

Authors' contributions

FR, FP, and MW made substantial contributions to the conception and design of the work; FR, MH, WvW, CF, and FP were involved in the acquisition and analysis of the data, FR, FP, WvW, NK, and MW performed the interpretation of data. All authors were involved in the draft and revision of the work.

All authors have approved the submitted version and any substantially modified version that involves the author's contribution to the study.

All authors have agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.

Acknowledgements

We are thankfully indebted to Dr. Birgit Lüttig for linguistic correction of the manuscript.

Finckh A, Gilbert B, Hodkinson B, Bae SC, Thomas R, Deane KD, et al. Global epidemiology of rheumatoid arthritis. Nat Rev Rheumatol. 2022;18:591–602.
Esposito AJ, Chu SG, Madan R, Doyle TJ, Dellaripa PF. Thoracic Manifestations of Rheumatoid Arthritis. Clin Chest Med. 2019;40:545–60.
Kadura S, Raghu G. Rheumatoid arthritis-interstitial lung disease: manifestations and current concepts in pathogenesis and management. Eur Respir Rev. 2021;30:21001.
Olson AL, Swigris JJ, Sprunger DB, Fischer A, Fernandez-Perez ER, Solomon J, et al. Rheumatoid arthritis-interstitial lung disease-associated mortality. Am J Respir Crit Care Med. 2011;183:372–8. 10.1164/rccm.201004-0622OC.
Sparks JA, He X, Huang J, Fletcher EA, Zaccardelli A, Friedlander HM, et al. Rheumatoid Arthritis Disease Activity Predicting Incident Clinically Apparent Rheumatoid Arthritis-Associated Interstitial Lung Disease: A Prospective Cohort Study. Arthritis Rheumatol. 2019;71:1472–82. 10.1002/art.40904.
Zhuo J, Zhang Q, Knapp K, Wang Y. Examination of Interstitial Lung Disease in Patients with Rheumatoid Arthritis – Prevalence, Time to Onset, and Clinical Characteristics. Ann Rheum Dis. 2020;79:24–5.
Smolen JS, Aletaha D, Bijlsma JW, Breedveld FC, Boumpas D, Burmester G, et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2010;69:631–7.
Juge PA, Granger B, Debray MP, Ebstein E, Louis-Sidney F, Kedra J, et al. A Risk Score to Detect Subclinical Rheumatoid Arthritis-Associated Interstitial Lung Disease. Arthritis Rheumatol. 2022;74:1755–65.
Moazedi-Fuerst FC, Kielhauser SM, Scheidl S, Tripolt NJ, Lutfi A, Yazdani-Biuki B, et al. Ultrasound screening for interstitial lung disease in rheumatoid arthritis. Clin Exp Rheumatol. 2014;32:199–203.
Pinal-Fernandez I, Pallisa-Nuñez E, Selva-O'Callaghan A, Castella-Fierro E, Simeon-Aznar CP, Fonollosa-Pla V, et al. Pleural irregularity, a new ultrasound sign for the study of interstitial lung disease in systemic sclerosis and antisynthetase syndrome. Clin Exp Rheumatol. 2015;33:S136–141.
Fairchild R, Chung M, Yang D, Sharpless L, Li S, Chung L. Development and Assessment of Novel Lung Ultrasound Interpretation Criteria for the Detection of Interstitial Lung Disease in Systemic Sclerosis. Arthritis Care Res. 2021;73:1338–42.
Wang Y, Chen S, Zheng S, Lin J, Hu S, Zhuang J, et al. The role of lung ultrasound B-lines and serum KL-6 in the screening and follow-up of rheumatoid arthritis patients for an identification of interstitial lung disease: review of the literature, proposal for a preliminary algorithm, and clinical application to cases. Arthritis Res Ther. 2021;23(1):212.
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheumatol. 2010;62:2569–81. 10.1002/art.27584.
Fischer A, Patel NM, Volkmann ER. Interstitial Lung Disease in Systemic Sclerosis: Focus on Early Detection and Intervention. Open Access Rheumatol. 2019;11:283–307.
Gargani L. Lung ultrasound: a new tool for the cardiologist. 2011;9:6.
Tardella M, Di Carlo M, Carotti M, Ceccarelli L, Giovagnoni A, Salaffi F. A retrospective study of the efficacy of JAK inhibitors or abatacept on rheumatoid arthritis-interstitial lung disease. Inflammopharmacology. 2022;30:705–12. 10.1007/s10787-022-00936-w.
Dougados M, Soubrier M, Antunez A, Balint P, Balsa A, Buch MH, et al. Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, cross-sectional study (COMORA). Ann Rheum Dis. 2014;73:62–8.
Fragoulis GE, Chatzidionysiou K. Lung cancer in rheumatoid arthritis. Is there a need for better risk assessment and screening? Clin Rheumatol. 2020;39:957–61.
Corrao S, Messina S, Pistone G, Calvo L, Scaglione R, Licata G. Heart involvement in rheumatoid arthritis: systematic review and meta-analysis. Int J Cardiol. 2013;167:2031–8.
Koduri G, Solomon JJ. Identification, Monitoring, and Management of Rheumatoid Arthritis-Associated Interstitial Lung Disease. Arthritis Rheumatol. 2023;75:2067–77. 10.1002/art.42640.

No competing interests reported.

Download PDF

Editorial decision: Revision requested
17 Jul, 2024
Editor assigned by journal
15 Jul, 2024
Submission checks completed at journal
15 Jul, 2024
First submitted to journal
02 Jul, 2024

You are reading this latest preprint version

A Novel screening protocol for early detection of lung involvement in seropositive and ACPA positive rheumatoid arthritis

Status:

Version 1

Abstract

Background

Methods

Statistics

Data management and ethics

Results

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1