expert roundtables

Interstitial Lung Disease in Patients With Rheumatoid Arthritis

by Leonard H. Calabrese, DO; Jonathan Kay, MD; and Vibeke Strand, MD, MACR, FACP

Overview

Rheumatoid arthritis–associated interstitial lung disease (RA-ILD) is a relatively rare entity that is linked to significant morbidity and mortality. Challenges relate to both diagnosis and treatment, and the treatment of the ILD is generally not as successful as that of the RA.

Q:

What are some of the challenges and opportunities in the approach to RA-ILD?

Vibeke Strand, MD, MACR, FACP

Adjunct Clinical Professor, Division of Immunology/Rheumatology
Stanford University School of Medicine
Biopharmaceutical Consultant
Palo Alto, CA

“RA-ILD is difficult to diagnose, assess, and manage.”

Vibeke Strand, MD, MACR, FACP

The ILD that is seen in patients with RA is very similar to the ILD that we see with other connective tissue diseases, although perhaps what differs from what we see in dermatomyositis or systemic sclerosis is that we can control RA-ILD to a better extent. RA-ILD is difficult to diagnose, assess, and manage. For patients with RA who are perhaps not as physically active as we would like, we might not even have an index of suspicion to ask the appropriate questions to uncover these types of symptoms. Overall, we know that patients with RA-ILD do not comprise a large group. Further, the ILD may not be as amenable to therapy, despite the fact that we are largely successful in treating the RA. Antifibrotic agents have been used in some cases of systemic sclerosis–related ILD, but it is unknown whether this would be beneficial in RA-ILD. The interleukin-6 (IL-6) inhibitor tocilizumab appeared to stabilize lung function (forced vital capacity), a secondary end point, in phase 2 and phase 3 trials in patients with systemic sclerosis, even though the primary end point (improvement in modified Rodnan Skin Score) was not met. Further, placebo-treated patients who were crossed over to tocilizumab also demonstrated a stabilization of forced vital capacity, suggesting a clear benefit of the therapy. Despite these results, the sponsor has chosen not to pursue the US Food and Drug Administration approval of tocilizumab for systemic sclerosis–related ILD. Nevertheless, we might still consider using an IL-6 inhibitor for a patient with RA-ILD, even if purely from the perspective of treating the RA.

Jonathan Kay, MD

Professor of Medicine and Population and Quantitative Health Sciences
Timothy S. and Elaine L. Peterson Chair in Rheumatology
Director of Clinical Research, Rheumatology
University of Massachusetts Medical School
Worcester, MA

“Once ILD is diagnosed in a patient with RA, it is important to establish an objective quantitative measure of pulmonary function, such as the diffusing capacity for carbon monoxide, so that the patient’s ILD can be followed longitudinally and monitored closely for any worsening.”

Jonathan Kay, MD

Because the prevalence of RA-ILD is relatively low, obtaining baseline chest radiographs may not be necessary for all patients. However, for patients with RA with pulmonary symptoms, such as dyspnea upon exertion, a high-resolution computed tomography (CT) is appropriate to better assess for structural evidence of ILD.  

Another question that arises in patients with RA-ILD is whether their ILD is attributable to RA, to the medications used to treat RA, or to some other factor. Should certain medications be avoided when treating RA because of their associated potential risk for the development of ILD? For instance, should we avoid using methotrexate to treat RA in a patient with ILD? If the ILD is related to RA disease activity, then treatment with methotrexate might be expected to result in improvement in or stabilization of ILD. Thus, once ILD is diagnosed in a patient with RA, it is important to establish an objective quantitative measure of pulmonary function, such as the diffusing capacity for carbon monoxide, so that the patient’s ILD can be followed longitudinally and monitored closely for any worsening.

Leonard H. Calabrese, DO

Professor of Medicine
RJ Fasenmyer Chair of Clinical Immunology
Director, RJ Fasenmyer Center for Clinical Immunology
Vice Chair, Department of Rheumatic and Immunologic Diseases
Cleveland Clinic Foundation
Cleveland, OH

“It is important to pay attention to the clinical signs and symptoms of ILD and to then avoid therapies that may exacerbate the ILD. For those patients with the most severe forms of ILD, I generally refer them to an ILD specialist.”

Leonard H. Calabrese, DO

Patients who are at increased risk for RA-ILD include men, smokers, those who are strongly seropositive, and individuals who have respiratory symptoms. These may be the categories for whom high-resolution CT screening may be a good first step. However, patients with RA who do not have symptoms of ILD may, with some frequency, have radiologic findings suggestive of fibrosis, which can make management decisions challenging. RA and CT changes suggestive of fibrosis are much more prevalent than is progressive fibrotic lung disease in RA; fortunately, the latter group of patients is relatively small. Clinically significant RA-ILD is estimated to occur in only about 5% to 10% of patients with RA; however, much larger percentages have radiologic findings suggestive of ILD. So, it is important to pay attention to the clinical signs and symptoms of ILD and to then avoid therapies that may exacerbate the ILD. The presence of pulmonary hypertension is a potential complication in those with advanced disease, but it is more common in patients with systemic sclerosis. I would agree with Dr Strand that, for patients who have mild symptoms, drugs such as IL-6 inhibitors, rituximab, and abatacept all have anecdotal positive results from small studies. However, no biologic agent is approved for this indication. For those patients with the most severe forms of ILD, I generally refer them to an ILD specialist. This is a very fast-moving scientific niche, with significant investigational use of drugs that include antimetabolites and antifibrotic agents.

References

Bendstrup E, Møller J, Kronborg-White S, Prior TS, Hyldgaard C. Interstitial lung disease in rheumatoid arthritis remains a challenge for clinicians. J Clin Med. 2019;8(12):2038. doi:10.3390/jcm8122038

Denton CP, Lin CJF, Goldin J, et al. Lung function preservation in a phase 3 trial of tocilizumab (TCZ) in systemic sclerosis (SSc). Eur Respir J. 2019;54(suppl 63):RCT1883. doi:10.1183/13993003.congress-2019.RCT1883

Duarte AC, Porter JC, Leandro MJ. The lung in a cohort of rheumatoid arthritis patients-an overview of different types of involvement and treatment. Rheumatology (Oxford). 2019;58(11):2031-2038. doi:10.1093/rheumatology/kez177

Duarte AC, Vinagre F, Soares J, Cordeiro A. Antifibrotics in interstitial lung disease related to connective tissue diseases - a paradigm shift in treatment and outcome. Acta Reumatol Port. 2019;44(2):161‐162.

Fischer A, Distler J. Progressive fibrosing interstitial lung disease associated with systemic autoimmune diseases. Clin Rheumatol. 2019;38(10):2673‐2681. doi:10.1007/s10067-019-04720-0

Fragoulis GE, Nikiphorou E, Larsen J, Korsten P, Conway R. Methotrexate-associated pneumonitis and rheumatoid arthritis-interstitial lung disease: current concepts for the diagnosis and treatment. Front Med (Lausanne). 2019;6:238. doi:10.3389/fmed.2019.00238

Khanna D, Denton CP, Lin CJF, et al. Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSSinate). Ann Rheum Dis. 2018;77(2):212-220. doi:10.1136/annrheumdis-2017-211682

Olson AL, Swigris JJ, Sprunger DB, et al. Rheumatoid arthritis-interstitial lung disease-associated mortality. Am J Respir Crit Care Med. 2011;183(3):372-378. doi:10.1164/rccm.201004-0622OC

Sparks JA, He X, Huang J, et al. Rheumatoid arthritis disease activity predicting incident clinically apparent rheumatoid arthritis-associated interstitial lung disease: a prospective cohort study. Arthritis Rheumatol. 2019;71(9):1472-1482. doi:10.1002/art.40904

Valenzuela C, Torrisi SE, Kahn N, Quaresma M, Stowasser S, Kreuter M. Ongoing challenges in pulmonary fibrosis and insights from the nintedanib clinical programme. Respir Res. 2020;21(1):7. doi:10.1186/s12931-019-1269-6

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