12. Dramatic improvement of chronic pleural effusion with abatacept treatment in longstanding rheumatoid arthritis, after chest sepsis during treatment with anti-TNF-α
Authors: McKee Natalie , McHenry Michelle 
Published: September 2019

Abstract

Introduction
Rheumatoid arthritis (RA) is a systemic inflammatory disorder, with various pulmonary manifestations, including parenchymal disease (interstitial lung disease), inflammation of the pleura (thickening and effusions), and inflammation of the airways and pulmonary vasculature (vasculitis and pulmonary hypertension).
These changes may reflect chronic immune activation, increased susceptibility to infection, or direct toxicity from disease modifying or biological therapy.
This case report describes a 69-year-old male with longstanding seropositive rheumatoid arthritis who developed severe pneumonia during adalimumab treatment, with subsequent persistent right basal pleural effusion. Treatment with abatacept has resulted in remission with significant decrease in size of the pleural effusion.

Case description
This patient attended the difficult asthma clinic and also ENT. Nasal polyps, troublesome post-nasal drip and persistent sinus infections led to 2 polypectomies and surgical turbinate resection.
Both rheumatoid factor and anti-CCP positive, he was treated with myocrisin, distamine and methotrexate sequentially, without satisfactory response. He was commenced on adalimumab 40mg subcutaneously fortnightly and achieved remission for 22 months.
Over a 6-week period he experienced increasing dyspnoea and productive cough. Adalimumab was omitted. Despite three oral antibiotics he continued to deteriorate and developed sepsis (white cell count 13, CRP 277) with an acute kidney injury. Chest radiograph showed right middle lobe infiltrates. CT chest showed no evidence of pulmonary fibrosis or bronchiectasis. Sputum was negative including for atypical infection. Interferon Gamma Release Assay (IGRA) was positive; sputum and urine culture for tuberculosis (TB) were negative after 6 weeks.
After the acute episode, repeat contrast CT chest demonstrated residual inflammatory changes in the right lower lobe with a small pleural effusion. Widespread synovitis developed; sulfasalazine was commenced with low dose oral corticosteroids. Interval imaging showed significant increase in effusion. Pleural aspiration confirmed an exudate with a total protein of 77 g/L and an LDH of 2364u/L. Glucose was undetectable and pH low consistent with a cellular metabolically active effusion. No organisms were identified.
Thorascopic biopsy revealed fibrinous pleuritis with chronic inflammation, but no evidence of malignancy, ILD, granulomata. Mycobacterial cultures were negative. Over the successive months the patient was managed with sulfasalazine, oral prednisone 5-7.5mg, intra-articular injections and he had a period of relative stability.
Joint disease then flared with dramatic synovitis, and a DAS-28 score of 6.46 was documented. Abatacept 125mg subcutaneously weekly was initiated with excellent clinical response. DAS-28 score 2.5 at 6 months, with no infective episodes, and the pleural effusion has significantly reduced in size.

Discussion
Symptomatic pleural involvement affects 3-5% patients with RA, is more common in older males and those with rheumatoid nodules. Most effusions are unilateral. In this case, effusion persisted after resolution of infection, and the clinical picture was not in keeping with parapneumonic effusion/empyema. Differential aetiologies included rheumatoid, tuberculosis (particularly in the setting of previous anti-TNF) and malignancy.
Typically, a rheumatoid effusion is sterile exudate with low pH, low glucose and elevated LDH. Rheumatoid factor may be present. White cell count and cell predominance is variable. Characteristic multinucleated macrophages and necrotic background debris may be seen.
Here, the pleural aspiration was not definitive in determining aetiology. Cytology confirmed large numbers of acute inflammatory cells accompanied by macrophages and mesothelial cells. Occasional multinucleated giant cells were seen; these have been described in both tuberculous and rheumatoid effusions. No alcohol/acid fast bacilli were cultured. A sample was sent for adenosine deaminase (ADA). Low ADA excludes tuberculous effusion however it is recognised that in rheumatoid disease it may be elevated. The ADA was elevated at 69 IU/L (0 - 45).
If the diagnosis remains unclear, as in this case, histological examination of the pleura may reveal replacement of the normal mesothelial lining with multinucleated giant cells and foci of palisading fibroblasts and lymphocytes surrounding necrotic centres, similar to rheumatoid nodules.
This gentleman’s biopsy demonstrated fibrinous pleuritis with chronic inflammation and some patchy mesothelial hyperplasia and no evidence of granulomatous inflammation. The pathologist stated that these appearances are observed in patients with rheumatoid arthritis but are not specific.
Most cases of rheumatoid pleuritis improve with treatment of the underlying arthritis; small, asymptomatic effusions don’t require specific intervention. However, persistent effusion can lead to pleural thickening and trapped lung; this would suggest that those with large or persistent effusion should be treated to avoid complication.

Key learning points
This patient developed a pleural effusion concurrent with sepsis, which persisted post infection and also experienced recurrent chest sepsis (although not as severe at time of admission) over the following 6-9 months. The effusion progressed with time in parallel with joint activity. The persistence of effusion was likely on the basis of RA, and establishing that this was the driving factor once infection/ other aetiology was excluded led to re-evaluation regarding biologic therapy with multi-specialty input.
After such significant infection and prolonged period of recovery and investigation, without resolution of the effusion, the patient, the rheumatology and the respiratory teams were each apprehensive about escalating immunosuppressive therapy. Initially, no further treatment with biologic was agreed. However, after several years of moderate ongoing disease activity and then significant flare, the cautious use of biologic agent was reconsidered. At this time, the patient’s quality of life was substantially diminished by his joint disease, and he made an educated decision to consent to treatment with abatacept.
The BSR biologic DMARD safety guidelines in inflammatory arthritis recommend using etanercept or abatacept as a first line biologic therapy in patients at high risk of infection, whilst American College of Rheumatology guideline regarding patients with RA and previous serious infection strongly recommends abatacept over TNF-α antagonist.
An increased risk of TB has been observed in patients receiving TNF-α antagonist. The British Society for Rheumatology (BSR) guideline regarding biologic DMARD in inflammatory arthritis recommends that all patients should be screened for latent TB with IGRA and chest radiograph, and treated prior to commencing treatment.

Conflict of interest
The authors declare no conflicts of interest.