Rheumatoid arthritis-interstitial lung disease: manifestations and current concepts in pathogenesis and management

Abstract

Rheumatoid arthritis (RA) is a systemic inflammatory disorder, with the most common extra-articular manifestation of RA being lung involvement. While essentially any of the lung compartments can be affected and manifest as interstitial lung disease (ILD), pleural effusion, cricoarytenoiditis, constrictive or follicular bronchiolitis, bronchiectasis, pulmonary vasculitis, and pulmonary hypertension, RA-ILD is a leading cause of death in patients with RA and is associated with significant morbidity and mortality. In this review, we focus on the common pulmonary manifestations of RA, RA-ILD and airway disease, and discuss evolving concepts in the pathogenesis of RA-associated pulmonary fibrosis, as well as therapeutic strategies, and have revised our previous review on the topic. A rational clinical approach for the diagnosis and management of RA-ILD, as well as an approach to patients with clinical worsening in the setting of treatment with disease-modifying agents, is included. Future directions for research and areas of unmet need in the realm of RA-associated lung disease are raised.

FIGURE 1

Suggested approach to the diagnosis of rheumatoid arthritis (RA) (and/or connective tissue disease (CTD))-associated interstitial lung disease (ILD). HRCT: high-resolution computed tomography; RF: rheumatoid factor; CCP: cyclic citrullinated protein; MDD: multidisciplinary discussion; UIP: usual interstitial pneumonia; NSIP: nonspecific interstitial pneumonia; OP: organising pneumonia; LIP: lymphocytic interstitial pneumonia; BAL: bronchoalveolar lavage. ^#: transbronchial biopsy, cryobiopsy or surgical lung biopsy, as per the treating clinician's discretion and/or MDD; elective surgical lung biopsy in patients may be considered if transbronchial lung biopsy and/or cryobiopsy is non-diagnostic in patients who are stable and are not at high risk for surgical complications; ^¶: findings can overlap with other radiographic patterns; ⁺: patients should be re-evaluated when appropriate if clinical symptoms or features of CTD develop during follow-up; ^§: pursue alternative diagnoses guided by appropriate clinical setting and guidelines (e.g. idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, sarcoidosis, etc.).

FIGURE 2

a) Axial and b) coronal computed tomography scans of usual interstitial pneumonia pattern in a 66-year-old Puerto Rican female known to have rheumatoid arthritis. Subpleural and basilar predominant reticulations, minimal ground-glass opacities, and honeycombing (arrow) are visible, as well as traction bronchiectasis.

FIGURE 3

Schematic illustration of the concepts in the pathogenesis of rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) with various therapeutic targets. The pathogenesis of RA is thought to involve an interplay between various risk factors (including smoking history, male sex and older age) and genetic predisposition (such as the shared epitope HLA-DRB1). In the lung, various environmental exposures causing airway and alveolar epithelial cell damage may lead to increased citrullination of proteins which, in an individual who is genetically predisposed, is thought to trigger an inflammatory process characterised by activation of cytokines, chemokines and growth factors, such as tumour necrosis factor (TNF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and interleukins (IL). These contribute to both proliferation and differentiation of fibroblasts, increased synthesis and deposition of extracellular matrix (ECM), and increased activity of matrix metalloproteinases (MMP), resulting in the development of ILD and pulmonary fibrosis. Fibroblasts in the synovial lining play a similar role in the pathogenesis of joint manifestations of RA. Various therapeutic targets include: 1) exposure avoidance via smoking cessation; 2) binding of CD20 receptor, leading to B-cell depletion (e.g. rituximab); 3) antiproliferative or cytotoxic agents (e.g. cyclophosphamide and mycophenolate); 4) TNF-α inhibitors (e.g. adalimumab, etanercept and infliximab); 5) pro-inflammatory IL-6 cytokine inhibitors (e.g. tocilizumab); and 6) antifibrotic agents (nintedanib and pirfenidone). Therapeutic agents not included in the figure include corticosteroids, which promote an anti-inflammatory response via inhibition of prostaglandin and leukotriene synthesis, and reduction of the number of circulating monocytes, as well as inhibiting the release of collagenase and lysosomal enzymes [71]. Also not pictured are nonbiologic (i.e. traditional or conventional) disease-modifying anti-rheumatic drugs, such as methotrexate, for which the exact mechanism in RA is unknown, but is thought to involve adenosine signalling via increase of adenosine levels leading to an intracellular cascade promoting an overall anti-inflammatory state [72]. CCP: cyclic citrullinated peptide; HLA: human leukocyte antigen. Reproduced and modified from [60] with permission.

FIGURE 4

Suggested diagnostic approach for management of lung disease progression versus pulmonary infection or toxicity induced by disease-modifying anti-rheumatic drugs (DMARDs) in a patient with pre-existing rheumatoid arthritis-associated interstitial lung disease (RA-ILD). HRCT: high-resolution computed tomography; GGOs: ground-glass opacities; BAL: bronchoalveolar lavage; TBBx: transbronchial lung biopsy; SLB: surgical lung biopsy. ^#: transbronchial biopsy or cryobiopsy, as per the treating clinician and/or multidisciplinary discussion; elective SLB in patients may be considered if TBBx and/or cryobiopsy is non-diagnostic in patients who are stable and are not at high risk for surgical complications.

FIGURE 5

Axial computed tomography scan demonstrating classic findings of follicular bronchiolitis in a 55-year-old male with rheumatoid arthritis. Note bilateral diffuse centrilobular peribronchial nodules <3 mm in size with branching structures corresponding to bronchial dilation and wall thickening (arrows). Image courtesy of Sudhakar Pipavath (University of Washington Medical Center, Seattle, WA, USA).