Multidisciplinary approach to connective tissue disease (CTD) related pleural effusions: a four-year retrospective evaluation

Background CTD-related pleural effusions are rare and challenging to diagnose. Our lung inflammation service (with expertise in rheumatology, interstitial lung disease and respiratory failure) works closely with the pleural team. This study aims to review the multidisciplinary approach to CTD-related pleural effusions at a tertiary centre. Methods All patients with CTD-related pleural effusions at St Thomas’ Hospital, London were included. Retrospective data were collected from Dec 2013 to 2016. Results The lung inflammation service performed an expert clinical assessment and targeted investigations. 11 patients (ages 23–77) were identified with CTD related pleural disease. 9 (82%) patients were given a new CTD diagnosis, with pleural disease as the first manifestation. The range of conditions were: rheumatoid arthritis [3] ,IgG4-related disease [2] ,adult Still’s disease [2] ,vasculitis [1] ,SLE [1] ,drug-induced lupus [1] ,and Behcet’s [1]. The pleural team review took place 1 day (median) after referral. 73% of diagnoses (8 patients) were achieved with local anaesthetic pleural interventions (a combination of: aspiration, drain, or percutaneous biopsy). This included 1 patient who required no pleural intervention. 1 required medical thoracoscopy, and 2 underwent thoracic surgery. Diagnoses were made by integrating all available evidence such as clinical assessment, imaging, and autoimmune serology. No diagnosis was achieved by pleural cytology or histology analysis alone. 8 (73%) were commenced on prednisolone acutely (vasculitis, SLE, drug-related lupus, 1 patient with rheumatoid arthritis, Behcet’s, 2 patients with Adult Still’s disease, 1 patient with IgG4-related disease). Of these 8, one patient with rheumatoid arthritis received IV methylprednisolone beforehand, one patient with IgG4-related disease was weaned off prednisolone to methothrexate, two patients with Adult Still’s disease were on colchicine as well, and one patient with Behcet’s was on cyclophosphamide as well. 7 (64%) were managed as outpatients; 4 required admission. The median time from pleural review to diagnosis was 53 days. Conclusions Diagnosis can be challenging in patients presenting with pleural disease as the first manifestation of a CTD. We recommend a multidisciplinary approach in management.


Background
A new pleural effusion may be caused by a wide range of conditions. The British Thoracic Society produced guidelines in 2010 recommending a systematic approach to achieve a diagnosis, aiming to streamline investigations and interventions [1]. Since then, the evidence base for managing malignant and infective effusions has developed through a series of clinical trials. In comparison, research on benign non-infective pleural effusions has been more limited [2]. A number of these are caused by connective tissue diseases (CTD).
Pleural effusions from CTD are caused by increased capillary permeability, as extravascular fluid moves from the lung's interstitium, across the mesothelium into the pleural space [3]. This may be due to a number of reasons [4], such as a pleural infiltrative process. In addition, circulating immune complexes that localise to the pleura, can activate the complement system causing endothelial injury. Enzyme and free radical release from white blood cells also accentuate the inflammatory process.
CTD-related pleural effusions are rare and challenging to diagnose. The most common CTDs to affect the pleura are rheumatoid arthritis and systemic lupus erythematosus (SLE) [1]. A prospective observational cohort study over 7 years at a specialist pleural unit identified 356 nonmalignant pleural effusions. 9.8% of these were given a diagnosis of inflammatory pleuritis, and 7.6% attributed to other diagnoses (including chylothorax, rheumatic causes, trauma, and drug-induced causes) [5].
The same unit described the value of a pleural specialist team to improve the efficacy and efficiency of managing patients with pleural disease [6]. In most pleural teams, the medical specialties involved are commonly: respiratory, oncology and palliative care. However, the pleural team in our centre works closely with the lung inflammation service, with expertise in rheumatology, interstitial lung disease and respiratory failure. This study aims to review the multidisciplinary approach to CTD-related pleural effusions at a tertiary centre. To our knowledge, there is no published evidence describing a multidisciplinary approach to CTD-related pleural effusions.

Study design
This study is a retrospective evaluation of cases. We reviewed electronic hospital records, imaging, blood tests, pleural fluid analysis and pleural biopsy analysis. Data were collected relating to CTD diagnosis, pleural and surgical interventions, and CTD specific systemic therapy.
As a retrospective service evaluation, written patient informed consent and regional ethics approval was not required.

Participants
All patients diagnosed with CTD-related pleural effusions at St Thomas' Hospital, London were included. We included patients referred to pleural clinic between November 2012 and 2016. These patients are usually referred by the general medical or rheumatology teams for a specialist pleural opinion when the etiology of the pleural effusion is unclear, or where there is an acute clinical concern. We excluded patients with a CTD attending pleural clinic with a pleural effusion due to other (non-CTD related) etiologies.

Interventions
Pleural aspirations, drains, biopsies and medical thoracoscopies were performed in the pleural clinic at St Thomas' Hospital in accordance with national guidelines [7,8]. Out of hours, aspirations and drains were performed by the radiology department.

Assessments
Statistical analysis was carried out using Microsoft Excel. Descriptive statistics were used to evaluable the service,  Pleural aspiration and chest drain 1 (9) Pleural aspiration and biopsy 1 (9) Pleural aspiration and biopsy, drain and VATS 1 (9) Pleural aspiration and medical thoracoscopy 1 (9) VATS, thoracotomy, pericardiectomy 1 (9)   *These were the key factors used by the mutldisciplinary team in securing a diagnosis and to summarise the clinical characteristics of the subjects.

Results
Eleven patients (ages 23-77) were identified with CTD related pleural disease (Table 1). They were seen by the lung inflammation service, who performed an expert clinical assessment and targeted investigations, usually after review by the pleural team. 9 (82%) patients were given a new CTD diagnosis, with pleural disease as the first manifestation. The range of conditions were: rheumatoid arthritis [3], IgG4-related disease [2], adult Still's disease [2], vasculitis [1], SLE [1], drug (carbamazepine)-induced lupus [1], and Behcet's [1]. The pleural team review took place 1 day (median) after referral. 73% of diagnoses (8 patients) were achieved with local anaesthetic pleural interventions (a combination of: aspiration, drain, or percutaneous biopsy). This included 1 patient who required no pleural intervention. 1 required medical thoracoscopy, and 2 underwent thoracic surgery ( Table 2). The patient who underwent a medical thoracoscopy (for pleural thickening) after an aspiration, had a final diagnosis of a rheumatoid arthritis associated pleural effusion. One patient who underwent thoracic surgery was referred directly to the surgical team, subsequently requiring a pericardiectomy for a diagnosis of IgG4-related disease. Another patient underwent VATS to rule out a pleural malignancy, before commencing treatment for a pleural effusion related to drug-induced lupus. Table 3 illustrates how diagnoses were made by integrating and analysing all available evidence, to include clinical assessment, imaging, and autoimmune serology. No diagnosis was achieved by pleural cytology or histology analysis alone. The pleural fluid pH was not measured for these patients (although it is available at our centre), as pleural infection was low on the list of differentials.
Eight (73%) were commenced on prednisolone acutely (vasculitis, SLE, drug-related lupus, 1 patient with rheumatoid arthritis, Behcet's, 2 patients with Adult Still's disease, 1 patient with IgG4-related disease). Of these 8, one patient with rheumatoid arthritis received IV methylprednisolone beforehand, one patient with IgG4-related disease was weaned off prednisolone to methothrexate, two patients with Adult Still's disease were on colchicine as well, and one patient with Behcet's was on cyclophosphamide as well. 7 (64%) were managed as outpatients; 4 required admission. The median time from pleural review to diagnosis was 53 days.

Discussion
In the work up for interstitial lung disease (ILD), assessment by a rheumatologist is recommended in suspected CTD [9]. The input of a rheumatologist is invaluable in providing an expert clinical review, then directing and interpreting autoimmune testing. Our centre has found this to be the casein managing CTD-related pleural effusions. The lung inflammation service was set up to assist the critical critical care team in managing severe respiratory failure; they now work closely with the pleural service as well. To our knowledge, this is the first published evaluation of a collborative approach for inflammatory pleural disease. Case reports of CTD-related serositis do not describe a similarly coordinated approach [10][11][12]. Our results suggest that the value of pleural fluid and tissue analysis is to exclude common conditions such as malignancy and infection, while a multidisciplinary approach integrating all available diagnostic information is needed for complex cases such as CTD related pleuritis.
In this service evaluation, the multidisciplinary approach to CTD-related pleural effusions has demonstrated efficiency in achieving a diagnosis in a median of 53 days from the first review by the pleural team. Pleural procedures were streamlined, with 73% of diagnoses being achieved by local anaesthetic interventions. 64% of cases were managed in the outpatient setting. Published data describe the outcomes of pleural service outcomes as a whole [13,14]. This is the first study to focus on the management of CTD-related pleural effusions.
The study was limited by the small number of cases, due to the rareity of CTD-related pleural effusions. A multi-centre collaboration to establish a larger database would facilitate advancement in best managing this complex patient cohort.

Conclusions
Diagnosis can be challenging in patients presenting with pleural disease as the first manifestation of a CTD. We recommend a multidisciplinary approach in management.
Abbreviations CTD: connective disease disease; ILD: interstitial lung disease; SLE: systemic lupus erythematosus; VATS: video-assisted thoracoscopic surgery SA is a rheumatology consultant. BL is a respiratory consultant with specialist interests in interstitial lung disease and respiratory failure. AW is a respiratory consultant with specialist interests in pleural disease and interstitial lung disease. LA is a respiratory consultant with specialist interest in pleural disease, Senior Honorary Lecturer at KCL, and the Chief Investigator for OPTIMUM trial. LA has secured funding from Becton and Dikinson Ltd. for the OPTIMUM trial.

Funding
Open access for this article was funded by King's College London.
Availability of data and materials Due to our local governance policy, we do not have permission to make the data sets on which the conclusions of the paper rely publicly available. A truncated data set (removing all potentially identifying features) may be made available on an individual request basis.
Ethics approval and consent to participate As a retrospective service evaluation, written patient informed consent and regional ethics approval was not required.

Consent for publication
Not applicable.