Rheumatoid Arthritis Extra-Articular Manifestations: Challenges of Interstitial Lung Disease

Although expansion of RA treatment options and adoption of treat-to-target approaches has improved joint-related outcomes and reduced the incidence and severity of some EAMs such as rheumatoid vasculitis and cardiovascular disease events, in the absence of randomized controlled trials, it is unclear whether available RA therapies have any effect on halting or reversing the lung manifestations of RA.4

The current treatment approach for RA-ILD focuses on extrapolation from studies in related diseases, such as scleroderma-ILDs, and include supportive care and anti-inflammatory therapies. Effective supportive care for patients with mild RA-ILD or for patients who have contraindication to pharmacotherapy include oxygen supplementation, vaccination for pneumonia and influenza, exercise rehabilitation, and prophylaxis for Pneumocystis jiroveci pneumonia in those with profound immunosuppression, as well as education for smoking cessation.3

Pharmacotherapy can be considered for patients with moderate to severe disease.3 Although glucocorticoids have been used as first-line therapy for RA-ILD, results from the PANTHER-IPF trial, which investigated the treatment of idiopathic pulmonary fibrosis with immunosuppressive agents, found increased morbidity and mortality.9 Results from this trial raises concern about the use of immunosuppressive agents in patients with RA with manifestations of IUP, as it has been reported that treatment for IUP with immunosuppression can increase susceptibility to infection.3

Available evidence does not recommend the use of cyclosporine and other calcineurin inhibitors because of their poor safety profile and lack of proven efficacy in the treatment of joint diseases.3 Although mycophenolate mofetil shows modest improvement in patients with RA-ILD, and cyclophosphamide has been used as a second-line agent to treat ILD unresponsive to steroids, no clinical trials specifically focused on the RA-ILD patient population have been performed with these agents. Similarly, little clinical data support the use of biologic agents for treating RA-ILD.3 In patients with severe rapidly progressing or end-stage RA-ILD, hematopoietic stem cell transplantation and lung transplantation are options that have been used successfully.10

In the absence of well-defined screening recommendations and diagnostic approach, physicians must raise their clinical suspicion of lung disease in patients with RA. Regularly monitoring patients with RA, particularly patients who have lung symptoms with unknown etiology, is critical for early diagnosis and treatment of RA-ILD. Advances are, however, being made, as biomarker studies, genomics, and application of new technologies, such as computer-generated quantified computed tomography assessment, are in development for clinical application.

“There are several groups looking at ways to identify [patients with ILD] early using combinations of blood biomarkers and different types of imaging,” said Dr Giles.

Several agents in early to mid-phase clinical development are in progress, evaluating the safety and efficacy of existing RA treatments, such as abatacept, and new treatments, such as pirfenidone.11,12 Studies evaluating the phenotype of ILD to better identify patients with RA who may be at risk or to better predict progression over time in patients with early RA are in progress.13,14 These advances may offer opportunity for early diagnostic assessment and treatment to improve patient outcomes, particularly for patients with high-risk disease.

Despite these studies, “an issue is that we don’t know whether early identification will have any impact since there are no established therapies proven to treat or halt ILD progression,” said Dr Giles, “particularly among those who may have mild subclinical disease that may never actually cause any symptoms”.


1. Marcucci E, Bartoloni E, Alunno A, et al. Extra-articular rheumatoid arthritis. Reumatismo. 2018;70(4):212-224.

2. Raimundo K, Solomon JJ, Olson AL, et al. Rheumatoid arthritis-interstitial lung disease in the United States: prevalence, incidence, and healthcare costs and mortality. J Rheumatol. 2019;46(4):360-369.

3. Esposito AJ, Chu SG, Madan R, Doyle TJ, Dellaripa PF. Thoracic manifestations of rheumatoid arthritis. Clin Chest Med. 2019;40(3):545-560.

4. Giles JT. Extra-articular manifestations and comorbidity in rheumatoid arthritis: potential impact of pre-rheumatoid arthritis prevention. Clin Ther. 2019;41(7):1246-1255.

5. Curtis JR, Sarsour K, Napalkov P, Costa LA, Schulman KL. Incidence and complications of interstitial lung disease in users of tocilizumab, rituximab, abatacept and anti-tumor necrosis factor α agents, a retrospective cohort study. Arthritis Res Ther. 2015;17:319.

6. Nakashita T, Ando K, Kaneko N, Takahashi K, Motojima S. Potential risk of TNF inhibitors on the progression of interstitial lung disease in patients with rheumatoid arthritis. BMJ Open. 2014;4(8): e005615.

7. Assayag D, Lee JS, King TE Jr. Rheumatoid arthritis associated interstitial lung disease: a review. Medicina (B Aires). 2014;74(2):158-165.

8. Nurmi HM, Purokivi MK, Karkkainen MS, Kettunen HP, Selander TA, Kaarteenaho RL. Variable course of disease of rheumatoid arthritis-associated usual interstitial pneumonia compared to other subtypes. BMC Pulm Med. 2016;16(1):107.

9. Idiopathic Pulmonary Fibrosis Clinical Research Network, Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366(21):1968-1977.

10. Cottin V, Brown KK. Interstitial lung disease associated with systemic sclerosis (SSc-ILD). Respir Res. 2019;20(1):13.

11. ClinicalTrials.gov. Phase ll Study of Pirfenidone in Patients With RAILD (TRAIL1). NCT02808871. https://clinicaltrials.gov/ct2/show/NCT02808871?term=rheumatoid+arthritis&cond=Interstitial+Lung+Disease&rank=6. Updated September 23, 2019. Accessed October 11, 2019.

12. ClinicalTrials.gov. APRIL (AbatacePt in Rheumatoid Arthritis-ILD) (APRIL). Nct03084419. https://clinicaltrials.gov/ct2/show/NCT03084419?term=rheumatoid+arthritis&cond=Interstitial+Lung+Disease&rank=4. Updated July 22, 2019. Accessed October 11, 2019.

13. ClinicalTrials.gov. Interstitial Lung Disease in Early Rheumatoid Arthritis (ILD-Early RA). NCT03977415. https://clinicaltrials.gov/ct2/show/NCT03977415?term=rheumatoid+arthritis&cond=Interstitial+Lung+Disease&rank=1. Updated June 6, 2019. Accessed October 11, 2019.

14. ClinicalTrials.gov. Rheumatoid Arthritis Patients at Risk for Interstitial Lung Disease (RAPID). NCT03297775. https://clinicaltrials.gov/ct2/show/NCT03297775?term=rheumatoid+arthritis&cond=Interstitial+Lung+Disease&rank=2. Updated October 2, 2018. Accessed October 11, 2019.