APRIL

Rheumatoid arthritis is a multi-system, autoimmune disease characterised by progressive inflammation and destruction of synovial joints and extra-articular structures. In recent decades, the natural history of rheumatoid arthritis (RA) has altered dramatically following a change in the treatment paradigm. The shift towards early, aggressive intervention with conventional disease-modifying drugs and the introduction of biologic agents into routine practice has substantially reduced the morbidity and premature mortality associated with RA secondary to effective abrogation of inflammation.

Lung disease in RA however remains an ongoing therapeutic challenge. The prevalence of clinically significant interstitial lung disease (ILD) in RA is up to 10% and is strongly associated with the presence of Anti-Citrullinated Protein Antibodies (ACPA). Patients with RA-ILD have an increased mortality compared to RA patients without ILD1. Median survival ranges between 3 and 8 years from time of diagnosis with RA-ILD.

The two most common forms of ILD are usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP), categorised by features on Computed Tomography scanning (CT) and histopathological evaluation. UIP is characterised on CT by the basal and sub-pleural predominance of reticular opacities, lung architectural distortion, traction bronchiectasis and honeycombing. NSIP demonstrates a uniform pattern of patchy ground glass, linear or reticular opacities but without honeycombing. UIP pattern RA-ILD is associated with a worse prognosis and increased mortality relative to NSIP, but is the most common subtype found in this group of patients.

The mechanism of RA-associated ILD is poorly understood. Epidemiological data demonstrates a strong association with smoking, high circulating levels of rheumatoid factor and the presence of ACPA. ACPA-positive lung disease can occur in the absence of joint disease, and citrullinated proteins have been found in the lungs and bronchoalveolar lavage (BAL) fluid of RA-ILD patients. Citrullination itself may be a trigger for immune dysregulation, and inflammatory markers IFN-_y and TGF-_ß2 were higher in BAL derived from patients with early RA and sub-clinical ILD that demonstrated radiographic progression. However, there is a limited evidence base on the relationship between biologic agents and RA-ILD. To date, there have been no trials specifically evaluating the impact of biological therapies on RA-ILD and the number of ILD exacerbations on such treatment is low in the general RA population.

The treatment of RA-ILD represents a management dilemma. Given that the therapeutic goal for RA is remission, clinicians increasingly face the challenge of choosing the optimal biologic agent in patients with RA-ILD and uncontrolled joint disease. There are no evidence-based guidelines to guide physicians in deciding whether to commence biologic therapy in this setting, or in selecting which drug is most appropriate. For patients whose joint disease is inadequately controlled with traditional non-biologic Disease-Modifying anti-rheumatic drugs (DMARDs), the choice of biologic DMARD is fraught with the risk of exacerbating their lung disease.

The purpose of this trial is to evaluate the impact of abatacept on RA-ILD, predominantly focusing on drug safety. A pilot study was developed to help inform this clinical question. An interventional trial was deemed to be necessary as the numbers of RA patients who have ILD and active joint disease that would qualify for abatacept treatment as routine standard of care would be too low to make an observational study feasible. Additionally, an interventional trial is advantageous in allowing standardized monitoring of the parameters of interest. Furthermore, as there is no standard of care in the management of RA-ILD, a head-to-head trial with an active comparator is not possible.

www.clinicaltrials.gov