Age of ILD onset is similar in patients with RA-UIP and RA-NSIP but duration of RA before ILD onset differs

Amigues, Isabelle

Chung, Jonathan H.

Demoruelle, M. Kristen

Fernández Pérez, Evans R.

Hobbs, Stephen B.

Huie, Tristan J.

Keith, Rebecca K.

Mohning, Michael P.

Olson, Amy L.

Solomon, Joshua J.

Swigris, Jeffrey J.

Yunt, Zulma X.

English

University of Kentucky

University of Kentucky UKnowledge Radiology Faculty Publications Radiology 2-22-2021 Duration of Rheumatoid Arthritis and the Risk of Developing Interstitial Lung Disease Michael P. Mohning National Jewish Health Isabelle Amigues National Jewish Health M. Kristen Demoruelle National Jewish Health Evans R. Fernández Pérez National Jewish Health Tristan J. Huie National Jewish Health See next page for additional authors Follow this and additional works at: https://uknowledge.uky.edu/radiology_facpub  Part of the Radiology Commons, and the Rheumatology Commons Right click to open a feedback form in a new tab to let us know how this document benefits you. Repository Citation Mohning, Michael P.; Amigues, Isabelle; Demoruelle, M. Kristen; Fernández Pérez, Evans R.; Huie, Tristan J.; Keith, Rebecca K.; Olson, Amy L.; Yunt, Zulma X.; Chung, Jonathan H.; Hobbs, Stephen B.; Swigris, Jeffrey J.; and Solomon, Joshua J., "Duration of Rheumatoid Arthritis and the Risk of Developing Interstitial Lung Disease" (2021). Radiology Faculty Publications. 30. https://uknowledge.uky.edu/radiology_facpub/30 This Letter to the Editor is brought to you for free and open access by the Radiology at UKnowledge. It has been accepted for inclusion in Radiology Faculty Publications by an authorized administrator of UKnowledge. For more information, please contact UKnowledge@lsv.uky.edu. brought to you by COREView metadata, citation and similar papers at core.ac.ukprovided by University of KentuckyDuration of Rheumatoid Arthritis and the Risk of Developing Interstitial Lung Disease Digital Object Identifier (DOI) https://doi.org/10.1183/23120541.00633-2020 Notes/Citation Information Published in ERJ Open Research, v. 7, issue 1, 00633-2020. Copyright © ERS 2021 This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. Authors Michael P. Mohning, Isabelle Amigues, M. Kristen Demoruelle, Evans R. Fernández Pérez, Tristan J. Huie, Rebecca K. Keith, Amy L. Olson, Zulma X. Yunt, Jonathan H. Chung, Stephen B. Hobbs, Jeffrey J. Swigris, and Joshua J. Solomon This letter to the editor is available at UKnowledge: https://uknowledge.uky.edu/radiology_facpub/30 Duration of rheumatoid arthritis and therisk of developing interstitial lungdiseaseTo the Editor:Rheumatoid arthritis is an autoimmune disease that classically presents as a symmetrical inflammatorypolyarthritis. Extra-articular manifestations are prevalent, with the lungs being the most common site [1],and interstitial lung disease (ILD) being the most severe form of pulmonary involvement. In some studies,the median survival of patients with rheumatoid arthritis and a usual interstitial pneumonia (UIP) patternon high-resolution computed tomography (HRCT) is around 3 years (similar to that in idiopathicpulmonary fibrosis (IPF) [2, 3]); however, in other studies, median survival is >7 years [4, 5]. Whenpresent, ILD accounts for 10–20% of all deaths in rheumatoid arthritis [6].There have been many reported risk factors for ILD in patients with rheumatoid arthritis, including malesex, the severity of rheumatoid arthritis and cigarette smoking [7–9]. High titres of circulatingautoantibodies (rheumatoid factor, anti-cyclic citrullinated (CCP) antibodies) may also predict ILD [10, 11].Rheumatoid arthritis–interstitial lung disease (RA-ILD) onset has previously been shown to occur in the6th or 7th decade [12], prompting many to think of ILD as a late-occurring phenomenon in rheumatoidarthritis. In a single-centre, retrospective study of 582 subjects with rheumatoid arthritis, of which only 46had RA-ILD, every decade increase in age at the time of rheumatoid arthritis diagnosis was associatedwith a 41% increased risk of RA-ILD [9]. Though it is occasionally reported in the literature that a longerduration of rheumatoid arthritis is a risk factor for ILD, there are no supporting data [13–15].The aim of this retrospective, single-centre study, was to evaluate duration of rheumatoid arthritis as a riskfactor for ILD and to determine whether duration of rheumatoid arthritis and age correlated with aradiological pattern of nonspecific interstitial pneumonia (NSIP) or UIP. Our institutional researchdatabase was queried for all subjects with a diagnosis of RA-ILD, with radiological UIP or NSIP pattern,between 2000 and 2014 (n=137). Subjects without sufficient data to determine a date of ILD diagnosiswere excluded, with the final cohort including 121 subjects. The date of ILD diagnosis was defined as theearlier between the first report of ILD on imaging, the first date an outside pulmonologist confirmed adiagnosis of ILD or the first visit with an ILD specialist. A “concomitant” diagnosis of rheumatoidarthritis and ILD is defined as both conditions being diagnosed within a year of each other to account forthe time from symptom onset to diagnosis. For initial analysis, all 121 patients in the cohort wereincluded. In assessment of ILD diagnosis concomitant to, or after rheumatoid arthritis diagnosis, patientswith preceding ILD diagnoses were excluded. Each subject’s HRCT scan was independently reviewed bytwo expert thoracic radiologists ( JC and SH) with all disagreements resolved through discussions untilconsensus was reached. Scans were classified as showing a pattern of UIP (RA-UIP, including both “UIP”and “probable UIP”) or NSIP (RA-NSIP). Pulmonary function tests performed within 6 months of ILDdiagnosis were recorded. This cohort has been previously reported on [4].Statistical analysis was performed use SAS statistical software, Version 9.3 (SAS, Inc.; Cary, NC, USA). Forinitial analysis, all 121 patients in the cohort were included. In certain analyses, we excluded subjectsdiagnosed with ILD >1 year prior to the diagnosis of rheumatoid arthritis. We assessed time-to-ILD usingthe product-limit method, displayed results using Kaplan–Meier curves and compared curves using the log@ERSpublicationsAge of ILD onset is similar in patients with RA-UIP and RA-NSIP but duration of RA beforeILD onset differs https://bit.ly/3lgjfDJCite this article as: Mohning MP, Amigues I, Demoruelle MK, et al. Duration of rheumatoidarthritis and the risk of developing interstitial lung disease. ERJ Open Res 2021; 7: 00633-2020[https://doi.org/10.1183/23120541.00633-2020].Copyright ©ERS 2021. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.https://doi.org/10.1183/23120541.00633-2020 ERJ Open Res 2021; 7: 00633-2020ORIGINAL RESEARCH LETTER0102030a)b) c) d)e) f) g)h) i) j)Subjects0246Subjects0510152025SubjectsAge at ILD diagnosis years20 25 30 35 40 45 50 55 60 65 70 75 80 85 20 25 30 35 40 45 50 55 60 65 70 75 80 30 35 40 45 50 55 60 65 70 75 8085Age at ILD diagnosis yearsAge at ILD diagnosis years0.00.20.40.60.81.0Subjects without ILD %0 10 20 30 40 500.00.20.40.60.81.0Subjects without ILD %0 10 20 30 40 500.00.20.40.60.81.0Subjects without ILD %0 10 20 30 40 50Duration after RA diagnosis years Duration after RA diagnosis years Duration after RA diagnosis years01020304050Time from RA diagnosis to ILD years–15–10 –5 0 5 10 15 20 25 30 35 40 45 50 55 –15–10 –5 0 5 10 15 20 25 30 35 40 45 50 55 –15–10 –5 0 5 10 15 20 25 30 35 40 45 50 55Subjects010203040Subjects02468SubjectsTime from RA diagnosis to ILD years Time from RA diagnosis to ILD yearsSubjectsMale sexAge at ILD diagnosis yearsAge at RA diagnosis yearsCurrent or former smokerCCP units RF IU·mL–1Methotrexate useBiologic useFVC % predDLCO % predTotalcohortUIP NSIP p-value12150%62.55261%138.48654.5564%66%70%49%94 2751%62.853.567%138.8772.963%64%70%50%44%61.745.641%137.3258.166%74%69%47%0.6630.6820.014*0.023*0.9500.0023*0.8220.3650.8640.632FIGURE 1 a) Baseline characteristics of cohort. Age at interstitial lung disease (ILD) diagnosis in rheumatoid arthritis (RA) patients. Histogramsdemonstrating number of patients at a given age (batched on 5-year intervals) at time of ILD diagnosis in b) all RA-ILD patients, and divided byhigh-resolution computed tomography (HRCT) radiological pattern of c) usual interstitial pneumonia (UIP) and d) nonspecific interstitialpneumonia (NSIP). Kaplan–Meier curves showing the time to development of ILD after the diagnosis of RA in e) all RA-ILD patients, and divided byHRCT radiological pattern of f ) UIP and g) NSIP. Duration of RA at time of ILD diagnosis. Histograms demonstrating number of patients at a givenRA duration, defined as years from diagnosis of RA (batched on 5-year intervals) at time of ILD diagnosis in h) all RA-ILD patients, and divided byHRCT radiological pattern of i) UIP and j) NSIP. CCP: cyclic citrullinated antibodies; RF: rheumatoid factor; FVC: forced vital capacity;DLCO: diffusing capacity of the lung for carbon monoxide. *: p<0.05.https://doi.org/10.1183/23120541.00633-2020 2ORIGINAL RESEARCH LETTER | M.P. MOHNING ET AL.rank test. We used Cox proportional hazards to analyse time-to-ILD while controlling for potentiallyinfluential and confounding variables. We did not use selection methods but chose to include in ourmodels clinically relevant potential confounders. We considered p<0.05 to represent statistical significance.As shown in figure 1a, the mean age at diagnosis of RA-ILD in our study was 63 years and did not differbetween UIP and NSIP. Subjects were more likely to be male (51%) and current or former smokers (61%).When divided by HRCT pattern, those with UIP were more likely to have smoked and had higherrheumatoid factor titres than subjects with NSIP. Treatments were similar between the two groups.Compared to subjects with RA-NSIP, those with RA-UIP were diagnosed with rheumatoid arthritis at anolder age (53.5±16 versus 45.6±14 years, p=0.01). After accounting for sex and smoking, this differenceremained significant (p=0.001).The range in age at diagnosis of ILD was similar between RA-UIP and RA-NSIP (figure 1b–d). Asignificant percentage of patients had ILD either predating (10%, n=12) or concomitant with (17%, n=20)the diagnosis of rheumatoid arthritis. 49% of subjects developed ILD either before or within 5 years of therheumatoid arthritis diagnosis and 67% of subjects developed ILD either before or within 13 years of beingdiagnosed with rheumatoid arthritis.To evaluate the duration of rheumatoid arthritis prior to the diagnosis of ILD, only those subjects whoseILD diagnosis was “concomitant” with or following the diagnosis of rheumatoid arthritis were analysed(n=109) (figure 1e–g). The mean duration of rheumatoid arthritis before the diagnosis of ILD was12.4 years. Compared to NSIP, UIP was diagnosed closer to the onset of rheumatoid arthritis (10.6 versus18.3 years from diagnosis of rheumatoid arthritis, p=0.025, figure 1h–j). When controlling for cofounderssuch as sex and smoking status, this difference remained significant (p=0.011). UIP was the ILD patternin 84% of patients whose ILD was diagnosed prior to or concomitant with rheumatoid arthritis. WhenILD was diagnosed 15 years after rheumatoid arthritis, patients were more likely to have NSIP than UIP(p=0.039).The development of ILD is a dreaded consequence of rheumatoid arthritis. Though there are establishedrisk factors, there are no good prediction models to help clinicians determine who with rheumatoidarthritis will get ILD and when in the course of rheumatoid arthritis their ILD will develop. Our resultsadd to this field of study by shedding light on the age at time of ILD diagnosis and its relationship to thetime of rheumatoid arthritis diagnosis with respect to radiological ILD pattern.Our study has limitations. This is a retrospective assessment of patients evaluated at a tertiary referralcentre and may not be representative of patients seen in a community pulmonary practice. We rely on thetime of clinical diagnosis of rheumatoid arthritis and ILD, and there is clear evidence that both synovitisand interstitial lung abnormalities can be present for months or years prior to a clinical diagnosis ofrheumatoid arthritis or ILD. We did not analyse the impact of rheumatoid arthritis disease activity, whichmay have impacted the timing, subtype and severity of the ILD diagnosis.In conclusion, we found that the pattern of ILD in patients with rheumatoid arthritis depends on the ageof rheumatoid arthritis diagnosis and the duration between the diagnosis of rheumatoid arthritis and thediagnosis of ILD. ILD diagnosis clusters around the time of rheumatoid arthritis diagnosis and has a meanage of onset similar to that seen in IPF. We also found that smokers are more likely to develop a UIPpattern of lung involvement, and the majority of subjects who developed ILD prior to rheumatoid arthritishad a radiological UIP pattern. We are currently not able to predict who with rheumatoid arthritis willdevelop ILD, but the knowledge that ILD clusters around the time of rheumatoid arthritis diagnosis with astrong predilection for the 7th decade of life can aid clinicians in a timely diagnosis of ILD in those atrisk.Michael P. Mohning1, Isabelle Amigues2, M. Kristen Demoruelle2,3, Evans R. Fernández Pérez 1,Tristan J. Huie1, Rebecca K. Keith1, Amy L. Olson1, Zulma X. Yunt1, Jonathan H. Chung4,Stephen Hobbs5, Jeffrey J. Swigris1 and Joshua J. Solomon11Division of Pulmonary, Critical Care and Sleep Medicine, Dept of Medicine, National Jewish Health,Denver, CO, USA. 2Division of Rheumatology, National Jewish Health, Denver, CO, USA. 3Division ofRheumatology, University of Colorado School of Medicine, Aurora, CO, USA. 4Dept of Radiology,University of Chicago, Chicago, IL, USA. 5Dept of Radiology, University of Kentucky, Lexington, KY,USA.Correspondence: Michael P. Mohning, National Jewish Health, 1400 Jackson St, Denver CO 80206, USA.E-mail: mohningm@njhealth.orgReceived: 31 July 2020 | Accepted: 21 Sept 2020https://doi.org/10.1183/23120541.00633-2020 3ORIGINAL RESEARCH LETTER | M.P. MOHNING ET AL.Conflict of interest: None declared.References1 Solomon JJ, Brown KK. Rheumatoid arthritis-associated interstitial lung disease. Open Access Rheumatol 2012; 4:21–31.2 Kim EJ, Elicker BM, Maldonado F, et al. Usual interstitial pneumonia in rheumatoid arthritis-associatedinterstitial lung disease. Eur Respir J 2010; 35: 1322–1328.3 Solomon JJ, Ryu JH, Tazelaar HD, et al. Fibrosing interstitial pneumonia predicts survival in patients withrheumatoid arthritis-associated interstitial lung disease (RA-ILD). Respir Med 2013; 107: 1247–1252.4 Solomon JJ, Chung JH, Cosgrove GP, et al. Predictors of mortality in rheumatoid arthritis-associated interstitiallung disease. Eur Respir J 2016; 47: 588–596.5 Park JH, Kim DS, Park IN, et al. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vasculardisease-related subtypes. Am J Respir Crit Care Med 2007; 175: 705–711.6 Yunt ZX, Solomon JJ. Lung disease in rheumatoid arthritis. Rheum Dis Clin North Am 2015; 41: 225–236.7 Demoruelle MK, Olson AL, Solomon JJ. The epidemiology of rheumatoid arthritis-associated lung disease. In:Fischer A, Lee JS, eds. Lung Disease in Rheumatoid Arthritis. Cham, Springer International Publishing, 2018; pp.45–58.8 Saag KG, Kolluri S, Koehnke RK, et al. Rheumatoid arthritis lung disease. Determinants of radiographic andphysiologic abnormalities. Arthritis Rheum 1996; 39: 1711–1719.9 Bongartz T, Nannini C, Medina-Velasquez YF, et al. Incidence and mortality of interstitial lung disease inrheumatoid arthritis: a population-based study. Arthritis Rheum 2010; 62: 1583–1591.10 Alexiou I, Germenis A, Koutroumpas A, et al. Anti-cyclic citrullinated peptide-2 (CCP2) autoantibodies andextra-articular manifestations in Greek patients with rheumatoid arthritis. Clin Rheumatol 2008; 27: 511–513.11 Mori S, Koga Y, Sugimoto M. Different risk factors between interstitial lung disease and airway disease inrheumatoid arthritis. Respir Med 2012; 106: 1591–1599.12 Kelly CA, Saravanan V, Nisar M, et al. Rheumatoid arthritis-related interstitial lung disease: associations,prognostic factors and physiological and radiological characteristics: a large multicentre UK study. Rheumatology(Oxford) 2014; 53: 1676–1682.13 Fong WW, Yoong JK. Interstitial lung disease and rheumatoid arthritis: a review. Proc Singapore Healthc 2015; 24:35–41.14 Iqbal K, Kelly C. Treatment of rheumatoid arthritis-associated interstitial lung disease: a perspective review. TherAdv Musculoskelet Dis 2015; 7: 247–267.15 Georgiadis AN, Metafratzi ZM, Drosos AA. Pulmonary abnormalities in patients with early and longstandingrheumatoid arthritis. J Rheumatol 2009; 36: 444–445.https://doi.org/10.1183/23120541.00633-2020 4ORIGINAL RESEARCH LETTER | M.P. MOHNING ET AL.

Duration of Rheumatoid Arthritis and the Risk of Developing Interstitial Lung Disease

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Duration of Rheumatoid Arthritis and the Risk of Developing Interstitial Lung Disease

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