Screening for rheumatoid arthritis-associated interstitial lung disease—a Delphi-based consensus statement
For this Delphi consensus statement, a panel of experts was formed, including seven specialists in rheumatology and clinical immunology, four specialists in respiratory medicine/pneumonology, and one specialist in thoracic radiology. The expert panel was selected based on their experience in the topic and their scientific merit. Objectives of this statement were determined a priori. Therefore, the modified Delphi technique in combination with the nominal group technique was used and consisted of five steps : Step 1 In the first session, the experts agreed on a moderator of the Delphi process (KH). Initially, literature databases were to be searched to identify relevant publications on epidemiology, diagnosis, monitoring methods, and screening for RA-ILD. All literature and background information were provided to the expert panel. Then the voting process was defined and the maximum number of rounds was determined. Polling was set to be anonymous via email and only the moderator was informed about the individual votes. The definition of consensus was predetermined and set to a level of agreement > 60% and consent with a median value of ≥ 3 on the four-point scale (fully agree, partly agree, partly disagree, fully disagree, and an option for abstention), with a lower interquartile range (IQR) of ≥ 3. Group responses were to be provided to all participants after each voting round. Step 2 The second step was concluded by describing five clusters for voting questions by the expert panel. The first cluster of questions was dedicated to symptoms and awareness of RA-ILD (I). The second cluster of questions was focused on patients with RA who present with respiratory symptoms suggesting RA-ILD (e.g., persistent cough and/or dyspnea on exertion; II). The third cluster was dedicated to RA patients without symptoms of RA-ILD but with risk factors (III). The most suitable diagnostic procedures for RA-ILD baseline examinations were subject to debate in the fourth cluster (IV). Cluster five was dedicated to the most suitable follow-up examination for patients referred for regular RA-ILD screening with normal baseline findings (V). Questions for each cluster were drafted based on the literature review. Step 3 After completing the anonymous voting, the group results of the voting were discussed in the panel. When no consent was reached, the expert panel defined another question based on the comprehensive discussion to resolve the discussion. Step 4 Another anonymous voting round was completed, followed by a discussion of the results and definition of further questions in case of insufficient consent on a question. Step 5 In a final anonymous voting round, the remaining questions were answered with consent, and consensual recommendations and an illustrative flowchart were created based on the voting results. 

In the first session, the experts agreed on a moderator of the Delphi process (KH). Initially, literature databases were to be searched to identify relevant publications on epidemiology, diagnosis, monitoring methods, and screening for RA-ILD. All literature and background information were provided to the expert panel. Then the voting process was defined and the maximum number of rounds was determined. Polling was set to be anonymous via email and only the moderator was informed about the individual votes. The definition of consensus was predetermined and set to a level of agreement > 60% and consent with a median value of ≥ 3 on the four-point scale (fully agree, partly agree, partly disagree, fully disagree, and an option for abstention), with a lower interquartile range (IQR) of ≥ 3. Group responses were to be provided to all participants after each voting round. 

The second step was concluded by describing five clusters for voting questions by the expert panel. The first cluster of questions was dedicated to symptoms and awareness of RA-ILD (I). The second cluster of questions was focused on patients with RA who present with respiratory symptoms suggesting RA-ILD (e.g., persistent cough and/or dyspnea on exertion; II). The third cluster was dedicated to RA patients without symptoms of RA-ILD but with risk factors (III). The most suitable diagnostic procedures for RA-ILD baseline examinations were subject to debate in the fourth cluster (IV). Cluster five was dedicated to the most suitable follow-up examination for patients referred for regular RA-ILD screening with normal baseline findings (V). Questions for each cluster were drafted based on the literature review. 

After completing the anonymous voting, the group results of the voting were discussed in the panel. When no consent was reached, the expert panel defined another question based on the comprehensive discussion to resolve the discussion. 

Another anonymous voting round was completed, followed by a discussion of the results and definition of further questions in case of insufficient consent on a question. 

In a final anonymous voting round, the remaining questions were answered with consent, and consensual recommendations and an illustrative flowchart were created based on the voting results. 

Cluster I The panel found consent and full agreement (100%) for the fact that a clinically significant RA-ILD is present in 7–15% of RA patients and is an important cause of mortality and loss of quality of life, and for the fact that preclinical RA-ILD poses an important factor in therapeutic decision-making in RA. Patients with RA should be asked for respiratory symptoms such as persistent cough and dyspnea on exertion, and undergo auscultation regularly (91% agreement). No consent was found for the additional use of a questionnaire to screen for respiratory symptoms of RA-ILD, since there is currently no approved questionnaire for this condition available. Questionnaires such as the Modified Medical Research Council, St. Georges Respiratory Questionnaire and the American College of Chest Physicians (ACCP) ILD questionnaire, etc., were designed for different purposes and do not specifically address the symptoms of RA-ILD. Cluster II The panel found consensus and agreement that patients who present with respiratory symptoms suggesting RA-ILD should be further examined with pulmonary function testing consisting of body plethysmography, spirometry, and diffusing capacity of the lungs for carbon monoxide (DLCO) testing as well as radiological assessment. High-resolution CT (HR-CT) without intravenous contrast is the radiological examination of choice for the detection of ILD. Chest radiographs have a low diagnostic yield for ILD and were considered an insufficient diagnostic tool in screening for RA-ILD. However, for differential diagnosis of general respiratory symptoms, e.g., diseases such as acute bacterial pneumonia, chest radiographs are a valid option. Cluster III Full consensus was found concerning the currently known risk factors for RA-ILD: smoking, elevated cyclic citrullinated peptide (CCP) antibodies and rheumatoid factor (RF), male sex, high disease activity, advanced age, and family history of RA-ILD. However, after two anonymous question rounds with subsequent discussions of the group vote, no consent was found on their individual value or regarding which combination of risk factors should prompt regular RA-ILD screening. The currently available data did not enable the panel to make an evidence-based statement. Therefore, until further evidence is provided, RA patients without respiratory symptoms but with known risk factor(s) for RA-ILD should be included into RA-ILD screening at the discretion of the treating physician on the basis of a case-by-case decision, which was consented and fully agreed upon (100%) by the panel in the third question round. Cluster IV Concerning examinations for RA patients without respiratory symptoms but with risk factors, the panel consented on pulmonary function testing (body plethysmography, spirometry), DLCO testing, and non-contrast HR-CT at baseline. In case of results suggesting RA-ILD at the baseline examinations, further management of the patient should be discussed in a multidisciplinary board (level of agreement 100%; full consent). Cluster V Concerning the most suitable follow-up examination for patients referred for regular RA-ILD screening with normal baseline findings, the panel agreed that regular HR-CT was not the most appropriate follow-up examination, but rather that follow-up on pulmonary function tests including DLCO and monitoring of clinical signs of RA-ILD should be performed. As no initial consent on the time period of follow-up examinations was found, the panel agreed that screening should be performed at least annually for patients with initially inconspicuous RA-ILD. Evidence on the repeated use of HR-CT was not regarded as sufficient; therefore, the panel voted that the decision to perform regular non-contrast HR-CT periodically in RA patients without respiratory symptoms but with known risk factor(s) for RA-ILD can be done at the discretion of the attending physician on the basis of a case-by-case decision. Furthermore, optional transthoracic ultrasound performed by an experienced examiner found consent and agreement in this context. An overview of the questions provided to the panel and the individual group outcome (level of agreement; consent) is provided as online supplemental material. Finally, the outcome of each cluster in the Delphi consensus was transcribed into a combined algorithm (Fig. ). 

The panel found consent and full agreement (100%) for the fact that a clinically significant RA-ILD is present in 7–15% of RA patients and is an important cause of mortality and loss of quality of life, and for the fact that preclinical RA-ILD poses an important factor in therapeutic decision-making in RA. Patients with RA should be asked for respiratory symptoms such as persistent cough and dyspnea on exertion, and undergo auscultation regularly (91% agreement). No consent was found for the additional use of a questionnaire to screen for respiratory symptoms of RA-ILD, since there is currently no approved questionnaire for this condition available. Questionnaires such as the Modified Medical Research Council, St. Georges Respiratory Questionnaire and the American College of Chest Physicians (ACCP) ILD questionnaire, etc., were designed for different purposes and do not specifically address the symptoms of RA-ILD. 

The panel found consensus and agreement that patients who present with respiratory symptoms suggesting RA-ILD should be further examined with pulmonary function testing consisting of body plethysmography, spirometry, and diffusing capacity of the lungs for carbon monoxide (DLCO) testing as well as radiological assessment. High-resolution CT (HR-CT) without intravenous contrast is the radiological examination of choice for the detection of ILD. Chest radiographs have a low diagnostic yield for ILD and were considered an insufficient diagnostic tool in screening for RA-ILD. However, for differential diagnosis of general respiratory symptoms, e.g., diseases such as acute bacterial pneumonia, chest radiographs are a valid option. 

Full consensus was found concerning the currently known risk factors for RA-ILD: smoking, elevated cyclic citrullinated peptide (CCP) antibodies and rheumatoid factor (RF), male sex, high disease activity, advanced age, and family history of RA-ILD. However, after two anonymous question rounds with subsequent discussions of the group vote, no consent was found on their individual value or regarding which combination of risk factors should prompt regular RA-ILD screening. The currently available data did not enable the panel to make an evidence-based statement. Therefore, until further evidence is provided, RA patients without respiratory symptoms but with known risk factor(s) for RA-ILD should be included into RA-ILD screening at the discretion of the treating physician on the basis of a case-by-case decision, which was consented and fully agreed upon (100%) by the panel in the third question round. 

Concerning examinations for RA patients without respiratory symptoms but with risk factors, the panel consented on pulmonary function testing (body plethysmography, spirometry), DLCO testing, and non-contrast HR-CT at baseline. In case of results suggesting RA-ILD at the baseline examinations, further management of the patient should be discussed in a multidisciplinary board (level of agreement 100%; full consent). 

Concerning the most suitable follow-up examination for patients referred for regular RA-ILD screening with normal baseline findings, the panel agreed that regular HR-CT was not the most appropriate follow-up examination, but rather that follow-up on pulmonary function tests including DLCO and monitoring of clinical signs of RA-ILD should be performed. As no initial consent on the time period of follow-up examinations was found, the panel agreed that screening should be performed at least annually for patients with initially inconspicuous RA-ILD. Evidence on the repeated use of HR-CT was not regarded as sufficient; therefore, the panel voted that the decision to perform regular non-contrast HR-CT periodically in RA patients without respiratory symptoms but with known risk factor(s) for RA-ILD can be done at the discretion of the attending physician on the basis of a case-by-case decision. Furthermore, optional transthoracic ultrasound performed by an experienced examiner found consent and agreement in this context. An overview of the questions provided to the panel and the individual group outcome (level of agreement; consent) is provided as online supplemental material. Finally, the outcome of each cluster in the Delphi consensus was transcribed into a combined algorithm (Fig. ). 

The aim of this Delphi consensus statement was to develop a stepwise screening algorithm for RA-ILD and to raise awareness among physicians regularly taking care of RA patients. Given the high mortality of RA-ILD and the availability of new therapeutic options such as nintedanib for the progressive pulmonary fibrosis phenotype of RA-ILD, early diagnosis of ILD is essential, and can be achieved by screening . However, the diagnostic methods and the timing of screening are still subject to debate. Monitoring of clinical signs (e.g., by auscultation) of possible lung involvement of RA at the time of diagnosis and during the regular follow-up visits was fully supported by the expert panel, as was the necessity of further investigations in case of suspicious respiratory symptoms (i.e., persistent cough or dyspnea on exertion). Further steps suggested are lung function testing with DLCO testing, body plethysmography, and HR-CT of the lung. DLCO has become an important standard in pulmonary function testing, next to forced vital capacity or total lung capacity . It is a strong and independent predictor of diffusion limitation and often the first sign of lung fibrosis. Particular interest should be given to lung auscultation, since Velcro crackles have been found to be a key finding in early fibrotic lung disease . It was discussed that combined measurements of lung volumes including diffusion capacity and the HR-CT should be used rather than the individual examinations alone. In case of non-corresponding results of lung function testing or HR-CT, a multidisciplinary discussion is mandatory to evaluate the presence of RA-ILD or differential diagnoses. This must be emphasized, since patients with RA may also suffer from coexisting ILD other than RA-ILD, with respective treatment indications. It is important to highlight that a multidisciplinary discussion should at least include specialists in pneumonology, rheumatology, and radiology, each with expertise in ILD . Using HR-CT to detect RA-ILD appears to be the best approach in terms of radiographic imaging. However, RA-ILD patterns vary, and may present as usual interstitial pneumonia (UIP), probable for UIP, non-specific interstitial pneumonia, organizing pneumonia, mixed patterns, unclassifiable patterns, and others . To avoid radiation exposure, the panel gave no general recommendation to screen all newly diagnosed RA patients but rather to focus on a population at higher risk. Therefore, the expert panel recommended evaluating risk factors for RA-ILD in each patient with RA, even in the absence of respiratory symptoms. Well established and known risk factors are current or former smoking (especially more than 25 packyears), age, male sex, high disease activity (e.g., by a Clinical Disease Activity Index [CDAI] score > 10), and a family history of and genetic predisposition for RA-ILD . A particular threshold for age as a risk factor has not yet been approved, but different studies found clinically significant RA-ILD from > 55 years upwards . Nevertheless, it has not yet been resolved how individual risk factors should be graded and translated into a clinically confident situation to further investigate for RA-ILD. Therefore, the panel concluded that the quantity and significance of existing risk factors for initiating continuous RA-ILD screening lies at the discretion of the attending physician on the basis of a case-by-case decision. From the panel’s perspective, there is currently not enough evidence to support any specific scoring or weighting of risk factors. These recommendations will be updated as soon as new and profound evidence is published about the classification of known RA-ILD risk factors. In this context it must be mentioned that a Spanish recommendation for ILD screening in RA patients was published after the Delphi consensus had been designed . In this Delphi consensus, risk factors were weighted and an arbitrary cut-off of 5 points was chosen for conducting ILD screening in RA patients. However, no confirmation of this score has been published so far, thus making it an expert recommendation based on experience rather than evidence. The important, yet unanswered question is whether or not more risk factors will forecast a higher likelihood of developing RA-ILD. If a patient qualifies for RA-ILD screening, a baseline pulmonary function test (including DLCO testing) and HR-CT should be performed, as suggested by the panel. For regular follow-up, we suggest looking for clinical sings of RA-ILD and to perform pulmonary function testing including DLCO on an annual basis. Another option is transthoracic ultrasound with evaluation of B lines. This technique has emerged over the past years as an alternative method to evaluate ILD in patients with connective tissue diseases, particularly systemic sclerosis , but also RA-ILD . However, transthoracic ultrasound is still rarely applied in the ambulant care of RA patients and might gain increased popularity in the future. The regular implementation of HR-CT was discussed critically in this particular situation, especially in patients without symptoms. Ionizing radiation is a general matter of concern, as it is a recognized cause of cancer ; however, there is also currently not enough evidence to suggest that screening using HR-CT could generate a prognostic benefit for the patient. Thus, there is currently no positive benefit–risk profile available to support regular HR-CT in patients with RA and risk factors for RA-ILD but without respiratory symptoms. Therefore, the necessity of regular HR-CT and the interval of diagnostic examinations are at the discretion of the attending physician on the basis of a case-by-case decision. If new evidence is published, this recommendation will be updated. In recent years, different studies have reported a MUC5B promoter variant rs5705950 as a rare but significant risk factor for developing RA-ILD, even in the absence of respiratory symptoms . Juge et al. also proposed a risk score to evaluate for subclinical RA-ILD, including sex, age at RA onset, RA disease activity using the Disease Activity Score-28 for Rheumatoid Arthritis with erythrocyte sedimentation rate (DAS28-ESR), and the abovementioned MUC5B rs35705950 genetic variant. However, the predictive value of this risk score still needs validation in prospective studies . A future perspective will be the announced European Respiratory Society (ERS)/EULAR connective tissue disease (CTD)-associated ILD management guidelines, which will include screening. Some limitations and weaknesses of this RA-ILD screening must be mentioned, especially the fact that the current evidence did not allow the expert panel to establish a risk score or a weighting of known risk factors for RA-ILD. Until additional data become available, the task of selecting RA patients based on risk factors for RA-ILD must be left in the hands of the caring physicians, thus making it open to interpretation. However, interdisciplinary awareness for RA-ILD as well as its proper tools for (differential) diagnosis are the major goals of our statement. 

This Delphi-based screening strategy was developed for early detection and ongoing surveillance of RA-ILD by a multidisciplinary team of pneumonologists, rheumatologists, and radiologists. The presented algorithm was designed to help carers of patients with RA to identify those at risk for RA-ILD and choose an applicable screening strategy for these patients. Furthermore, disease awareness for RA-ILD among carers and patients is of utmost importance. Since risk factors for RA-ILD are well known but cannot be weighted at the moment, an updated version of this recommendation will be necessary when further evidence on this topic is published. 

Additional Table 1: Overview of the questions provided to the expert panel and the individual group outcome 

