- Indian Rheumatology association
C B Mithun MD, DM, MRCP (UK), FRCP (Edin.)
Professor, Department of Clinical Immunology and Rheumatology, Amrita Institute of Medical Sciences, Kochi, Kerala, India.
Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is among the most severe and complex extra-articular manifestations of RA. It poses significant diagnostic, therapeutic, and prognostic challenges. With rising awareness and enhanced imaging sensitivity, the burden of RA-ILD becomes more apparent in clinical practice, raising concerns regarding drug safety, efficacy, and monitoring strategies.
RA-ILD affects an estimated 10–30% of RA patients, though the true prevalence is likely underestimated due to subclinical disease. Known risk factors include smoking, older age, male sex, and high levels of rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) antibodies. Disease severity varies; some patients remain asymptomatic, with incidental findings such as fine basilar crackles on examination or subtle changes on imaging. Others present with chronic cough or exertional dyspnoea. The clinical course of RA-ILD is unpredictable—some patients remain stable for years while others experience acute exacerbations or progressive decline, underscoring the need for regular monitoring with pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT). The most frequent HRCT pattern observed in RA-ILD is usual interstitial pneumonia (UIP), followed by nonspecific interstitial pneumonia (NSIP) and organizing pneumonia (OP). Other patterns are observed less frequently, and the UIP pattern is associated with a worse prognosis compared to other subtypes.
The treatment should be considered upon diagnosis of RA-ILD, particularly when the disease is symptomatic or progressive, as early intervention may reduce mortality risk. Although NSIP and OP ILD patterns are more likely to respond to immunosuppressive medications than UIP, the treatment decision shouldn’t be based solely on HRCT ILD pattern. In fact, the progression of ILD and the severity of lung involvement (e.g., >20% lung involvement on HRCT chest) are the two main factors to consider when making treatment decisions. For example, evidence of progression, such as a decline in PFTs (a 10% decrease in forced vital capacity [FVC] or a 15% decrease in diffusing capacity of the lung for carbon monoxide [DLCO]) or worsening HRCT findings, indicates a need for treatment, even in the absence of symptoms. Those with asymptomatic or subclinical ILD may not need immediate treatment at all; however, careful monitoring is necessary for ILD progression.
The management of RA-ILD is not based solely on ILD pattern or severity. A broader perspective is needed—one that considers systemic RA activity, particularly active arthritis, and patient comorbidities. In symptomatic or progressive ILD, mycophenolate mofetil (MMF) or rituximab are preferred first-line therapies. Azathioprine may be used if MMF or rituximab are not suitable. When both joint and lung disease are active, rituximab is often favoured due to its efficacy in both areas. A combination of MMF and rituximab may be considered in more aggressive cases. Short courses of corticosteroids are frequently used during induction. In severe or rapidly progressive cases, cyclophosphamide may be utilized in induction, though with caution due to its toxicity. Smoking cessation and vaccination against influenza and pneumococcus are critical supportive measures for all patients.
Methotrexate (MTX) has historically been viewed with caution due to concerns about pulmonary toxicity. However, current evidence suggests that MTX is not a significant risk factor for the development or progression of RA-ILD. In patients with well-controlled RA and stable ILD, MTX can often be continued. Nevertheless, in rare cases where RA first presents as symptomatic ILD, MTX may be avoided, especially in the acute phase, due to the possibility of methotrexate pneumonitis, which may mimic or exacerbate ILD and be difficult to distinguish from an acute ILD flare.
Conventional DMARDs such as sulfasalazine and hydroxychloroquine are regarded as safe in RA-ILD but show limited efficacy in lung disease. Leflunomide has been associated with ILD exacerbations in rare instances and necessitates close monitoring. Among biologics, aside from rituximab, tocilizumab and abatacept are deemed safe in RA-ILD. However, it remains unproven whether they have any clinically significant effects on RA-ILD. Anti-TNF agents have been linked to ILD worsening in case reports. While real-world data are inconclusive, their use is generally avoided in RA-ILD until more substantial evidence emerges. JAK inhibitors, such as tofacitinib and baricitinib, seem safe according to early reports, but their efficacy on RA-ILD requires more data.
Traditional immunosuppression may be inadequate for patients with progressive fibrosing RA-ILD. Nintedanib, an antifibrotic agent approved for progressive fibrosing ILD, including RA-ILD, can reduce the rate of FVC decline. While its tolerability profile (e.g., diarrhoea, transaminitis) should be considered, it provides an essential addition to the therapeutic armamentarium for RA-ILD.
Managing RA-ILD requires a multidisciplinary approach that balances control of articular disease with the preservation of lung function. Treatment decisions should be individualized based on the ILD pattern, severity, and patient-specific factors, guided by the latest evidence and clinical guidelines.
